Important Notice: Alzheimer Research Forum does not provide medical advice nor promote any product or service. The contents are for informational purposes only and are not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on this web site. The views of individuals quoted on this site are not necessarily those of the Alzheimer Research Forum.

This page is devoted to the presentation and exchange of ideas regarding novel hypotheses, hunches, theories-in-progress, etc. All established hypotheses started out as someone's wild notion, and this page pays tribute to them by creating a forum where people with original or unconventional ideas can publicly present and discuss them. See also our AD Hypotheses page.

Submit a hypothesis. Comments are definitely encouraged!

(We also recognize that it is a subjective exercise to decide whether a hypothesis is still half-baked or fully formed and testable. Your opinions on this matter are also welcome.)

External Toxic Factors
Borrelia and AD
The Toxic Effects of Mercury and AD
Radiation Exposure and Alzheimer's Risk
Multiple Chemical Sensitivity
Refined Food Oils Contribute to AD and ADHD
Tellurium and Alzheimer's?
Nicotine and AD

Treatment-based Discovery
Folic Acid for Symptomatic Relief of “Sundowning” Syndrome
Agitation and Alerting Agents
Gingko Biloba and Yerba Mate Tea
Effect of Sleeping Pill Zolpidem in an AD Patient
Omega3 and Vitamin E
Marijuana and AD
Turmeric and Alzheimer's
Vitamin C IV

Links Between Alzheimer's and Other Major Diseases
Alzheimer's and Lyme Disease
AD and MS, CFS and Atheroscleorisis
Stereotactical Phenomenon in TBI Biomechanics
AD and Vascular Dementia Connection
Alzheimer's and Schizophrenia
Alzheimer's and Asthma link
HSV-1 Is Frequently Found in the Brain

Other Roles of AβPP, Presenilin and Aβ Peptide
Presenilin Hypothesis
Growth or No Growth: APP Weighs the Question
Novel enzyme involved in Ab vaccine action?
Presenilins and transglutaminase regulation
Amyloid b peptide as infectious agent, analogous to prion?
Investigation of the role of APP during cell transformation

Physiological Processes Gone Awry
Ependymal Stem Cell Niche Disruption Hypothesis
Hyponatremia and Alzheimer's
Involvement of RELB in AD
Cholesterol and AD
Ontogenesis, Breast Milk Childhood Intelligence and AD
Secretory Vesicle Defect and AD?
Glycation theory of aging

Case Studies
The May B Memory: Case study of patient May B. that raises questions on Alzheimer's and Memory Loss
Recovery of Function in AD Patient Following a Stroke
Hip Surgery and AD?
The Irruption into Profound Dementia of a Window of Sudden Lucidity

Hypothesized Treatments
Alzheimer Disease Treatment

External Toxic Factors

Borrelia and Alzheimer disease—Posted 21 August 2005
By Liz Shepherd

Here in South Carolina, several patients diagnosed with Alzheimer disease actually had DNA PCR positive Borrelia cultures grown from their brains. The symptoms for these illnesses do in fact overlap. Many psychiatrists now say that all brain disease is infectious. Have you actually LOOKED for a common denominator? Have all Alzheimer brains been checked for Borrelia? My guess is you may be very surprised to find out what is causing Alzheimer's.

See related Live Discussion: The Pathogen Hypothesis
See related Forum Discussion: The Pathogen Hypothesis-Challenging the Primacy of Genetics in Late-Onset Alzheimer Disease
See Mattsson N, Bremell D, Anckarsater R, Blennow K, Anckarsater H, Zetterberg H, Hagberg L. Neuroinflammation in Lyme neuroborreliosis affects amyloid metabolism. BMC Neurol. 2010 Jun 22;10(1):51. Abstract

The Relationship Of The Toxic Effects Of Mercury To Exacerabation Of The Medical Condition Classified As Alzheimer's Disease—Posted 13 August 2001
By Boyd E. Haley

Abstract: Mercury in ionic and vapor form when exposed to normal brain tissue is capable of causing the same biochemical aberrancies found in Alzheimer's diseased (AD) brain with the rapid inactivation of tubulin, creatine kinase and glutamine synthetase. Mercury exposure to neurons in culture is also capable of effecting elevated production of amyloid protein, hyper-phosphorylation of Tau and the stripping of tubulin from neurofibrils causing the production of neurofibillary tangles. I propose that mercury, and other supporting factors, that have more specificity for thiol-sensitive enzymes such as tubulin and creatine kinase are the major environmental toxicants that are the etiological source of AD. This hypothesis is supported by the genetic susceptibility expressed through the APO-E gene family. Here a reduction of APO-E gene types carrying cysteines decreases the ability to remove mercury from the cerebrospinal fluid and increases the risk of AD. See More

Radiation Exposure and Alzheimer's Risk —Posted 19 October 2000

I am trying to determine whether my father's occupation placed him at increased risk for Alzheimer's disease/related dementia. Dad died two years ago of complications of AD just after he turned 67, following a career as an engineer (biomedical/nuclear/electrical) working at, among other facilities, one of the nuclear reactor sites presently in the news for worker health hazards. Additionally, he spent two years in survey activities of many uranium mill tailing sites across the country. I'm just beginning to research this and I've found references to cancers, pulmonary complications, and skin involvement, but nothing on brain/neurologic damage arising from exposure to excessive radiation levels. What literature I have read so far indicates brain/nervous tissue is often spared damage by radiation levels that commonly damage other body tissues. However, since there is no known prior history of dementias in my father's family, and since Dad was so young (in retrospect, I believe his first symptoms probably appeared in his mid-50s, 7-9 years before his death), our family has long suspected his dementia may well be the result of an occupational exposure to radiation or heavy metals. Unfortunately, since Dad's work was classified, I have little additional data to help me determine if his occupation played a role in the development of his dementia. I found your website during an online search and it seems (please excuse my ignorance) you are on the forefront of scientific investigation into dementias...so I am hoping at least one of your members can offer me some insight into this or direct me to someone who might be able to. Specifically, I am wanting to know if a pattern of dementias has been identified among those who work(ed) at reactor sites, weapons production plants, mill tailing sites, etc. I would be grateful for any advice you can offer. Sincerely, (Ms.) Robin Santos <MDocuments@aol.com>

Comment by Peter Davies: —Posted 19 October 2000

As far as I am aware, there has been no real investigation of the possible link between AD and ionizing radiation. Of course, people exposed to high levels of radiation do not generally survive long enough to develop AD: they die of cancer first. But the epidemiologic studies should be there if the link was there: enough radiation to raise the risk for cancer in a given population would be expected to cause focal accumulations of AD cases, and this is something that has been looked at in some detail, especially in the UK. Some clusters of cases have been found, but these have always proved to be the result of inherited disease. Families tend to stay reasonably close to each other, or did, prior to the current generations. I recall reading about a major accident at the large uranium processing facility in northwest Britain in the 50's The place was called Windscale, and there was a fire in a reactor that burned out of control for a while, because no one had any idea how to put it out without the risk of explosion. Since the rigorous epidemiologic studies looking for AD were performed in England and Scotland in the 80's and 90's, one would have expected this to show up, if the link was there. Very significant contamination of the environment did occur.

A suggestion to the people who performed the epidemiologic studies in the UK in the last few decades: get hold of a map showing where high levels of iodine and cesium contamination occured following the accident at Windscale. see if there is a match. It should also be possible in the smaller European countries to look at the workers in nuclear power plants or processing facilities to see if there is any increase in the incidence of AD. These workers are monitored to look for increased incidence of cancers, and their health records should be easy to get.

Peter Davies, Ph.D.
Resnick Professor
Dept of Pathology
Albert Einstein College of Medicine

Reference: —Posted 1 April 2003

Reference: —Posted 21 August 2003

Multiple Chemical Sensitivity—Posted 6 February 2002

Refined Food Oils Contribute to AD and ADHD—Posted 28 April 2003.

My hypothesis, "Essential Fatty Acids and Brain Development," describes the role of vitamin E-deficient, refined edible oils in causing Alzheimer's and also ADHD. The mechanism is simple. It involves lipid peroxidation of neuronal and retinal membranes, which depletes those tissues of long-chain omega-6 and omega-3 EFA. More importantly, it releases cytotoxic aldehydes, especially 4-hydroxy nonenal, and even the highly toxic acrolein, into synaptic interiors and synaptic clefts. There, these aldehydes attack mitochondria, glucose entry mechanisms, and glial glutamate receptors, while synaptic AbPP a-secretase enzyme will be subject to inactivation by such aldehydes, thus preserving intact b sequences in AbPP fragments. Synaptic loss from local aldehyde toxicity will precede much-later amyloid fibril attack on the long-suffering synaptic membranes.

The same oils ward off cancer, diabetes, and coronaries, all of which are notably absent in properly diagnosed AD cases. Young people using refined oils are invariably forgetful, irritable, night-blind, and glare-sensitive, the first two symptoms responding swiftly to vitamin E/fish oil capsules.

I believe ADHD is caused by prenatal exposure to such oils, which leaves the mother with lifelong photophobia and some degree of night-blindness, even if she switches to olive or cold-pressed oils, and sees her memory and irritability improve. Steam-deodorization of cottonseed and other oils was invented about 1900 by Wesson. A Smith and Wesson may beat four aces, but odorless seed oils have killed and enraged more people than revolvers ever did. Early identification of vegetable oil syndrome, and treatment with vitamin E and fish oil, should slow or stop AD. Such treatment assists ADHD with better results than are seen with empiric medical chemicals devised and employed by medical folks who can't be accused of failing to think outside the square, since they don't know there is a square!!

I recommend to all science hopefuls, as a warning, all and any papers based on the irrational medieval urge to treat diseases before their causes are worked out. As an antidote to this ubiquitous pseudo-modern, neo-medieval therapomania, I recommend to all Parkinson's researchers an excellent paper on the disease, published in London in 1817. The author, a mere general practitioner with broad scientific interests but no "advanced degrees," was titled "An Essay On The Shaking Palsy," and it concludes with a warning to Apothecaries, Herbalists and other Pretenders to Science: "Until more is known respecting the ORIGINS of this disorder, it would be premature to attempt treatment"—(or words to that effect). Parkinson realized that he was seeing a new disease, although isolated cases had been recorded in Germany and Switzerland some decades earlier. Importantly, he missed what Charcot noticed many years later—a characteristic Parkinson's personality—"vigilant, watchful, and alert."

Later still, clinical depression (with underlying anxiety or obsessiveness) was noted to be common before disease onset, and then The Big Clue arrived in the 1970s, with the seminal observation of associated glucose intolerance, which is causally related to 1) saturated fat intake and 2) chronic anxiety. Since 2) is itself caused by 1) during pregnancy (my research interest), the rise of PD in the West can with some certainty be blamed on rising saturated fat consumption since about 1720. PD is a second-generation phenomenon, since a calm mother of the first generation, eating fat in pregnancy, will bear anxious, low-dopamine offspring highly predisposed to PD, which the calm mother is unlikely to develop herself. After several further generations of fat consumption and anxiety disorders, increasing familial and multigenerational aggregation of PD will lure amateur speculators towards an ever-retreating genetic mirage, on a fool's errand that James Parkinson would have smiled at.

The same story of anxiety, obsessionality, and Parkinson's will be found in non-Western societies wherever much lard, beef fat, lamb fat, ghee, cheese or coconut cream is consumed in pregnancy, e.g., the Parsee community in Bombay, or the psychiatric community in Sri Lanka! The same combination of fatty diet and lifelong stress kills off most potential PD cases in midlife, through aggravated heart disease, diabetes, severe stroke, and accelerated cancers, which are also common in actual PD cases, as many have noticed. The worse the anxiety, the less the fat required to get the disease. Saturated fats convert to monounsaturates, which infest all plasma and intracellular membranes as a result, and together with low EFA levels, this membrane pathology causes mitochondrial uncoupling and superoxide formation. The consequences in GPX-deficient regions of substantia nigra can be imagined, and, of course, iron will get into the aqueous-oxidation act once glutathione drops sufficiently.

If one knows WHY it gets into the act, one will refrain from devising alchemical iron-trappers, and instead put the patient on a membrane-friendly, low-fat, EFA-rich, antidiabetic diet, based on an understanding of the "ORIGINS of the disease." (Applause heard from Dr. J. Parkinson.) The anxiety component is efficiently corrected with 5-10 gm of Inositol powder daily, which fixes the otherwise lifelong inositol deficiency seen in anxious people, thereby restoring serotonin, noradrenaline, and acetylcholine function, and also calming the HPA stress axis and lowering cortisol neurotoxicity in hippocampus. Inositol may help dopamine formation via tyrosine hydroxylase effects, rather like nicotine (!), and mysteriously increases dopamine receptor numbers in the striatum, at least in rats. Iron enthusiasts may care to read Sidney Fahn's 1988 paper on vitamin C in Parkinson's; maybe it helped to keep up the level of reduced glutathione, which would prevent iron release. Dietary vitamin E intake protects against PD (Rotterdam Study), yet vitamin E given alone fails to help (DATATOP Study). It helps to know that natural vitamin E intake reflects PUFA intake, and it is the essential fatty acids that keep mitochondrial membranes healthy and efficient, thus preventing uncoupling and aqueous oxidation. Some 10-15 percent of PD cases are long-term nonprogressors, who may have adopted a low-fat EFA-rich diet, with its mitochondrial benefits. Note the role of protein deficiency in depressed PD cases, who often have silent diabetes, periodontal disease, and no teeth to bite meat with. Australian war heroine Nancy Wake (91) in London, cheerful as ever, enjoys her "two googy eggs" for breakfast, getting a good supply of sulphur amino acids wherewith to make glutathione to ward off aqueous oxidation. Alzheimer's, in contrast, is clearly a lipid peroxidation disease, caused by refined vitamin E-deficient vegetable oils. Here, vitamin E may do some good, preferably with fish oil accompaniment.

I suspect that mid-life anxiety sufferers, already feeling the effects of long-term cortisol toxicity in hippocampus, go down much faster with Alzheimer's if they take to refined oils. Ab plus cortisol is a Devil's Brew. The intriguing thing about fats and oils is their opposite behavior inside and outside the body; saturated fats sit there at room temperature for months or years without going off, but 1) eat them and 2) breathe oxygen, and you'll get mitochondrial oxidation from uncoupling. Oils do the very opposite, being unstable on storage; yet, once in place in our mitochondrial membranes, the EFA prevent uncoupling! Those with "advanced degrees" will note that a slight degree of membrane lipid peroxidation is wisely used by Mother Nature to regulate cell division and apoptosis (via 4-hydroxy nonenal release), so fatty diets will both abolish useful (physiological) membrane peroxidation and cause harmful intracellular aqueous oxidation.

Unthinking vitamin E supplementation will worsen this bad situation in stressed and fat-eating folks, hastening their demise through accelerated tumor growth or undeleted autoimmune clones. The Prophet says—Eat Almonds for Good Memory! If you want vitamin E, eat it with the EFA that Mother Nature is pleased to supply, and your problems are over.—Robert Peers, Melbourne, Australia.

Tellurium and Alzheimer's? —Posted 6 February 2002

I can't decide if the red orange in this Lewy Body I am looking at is an isatin of benzene, has that yellow isatin found high in Parkinsonians, or is the red congo that binds with Map. Aspergillus terreus is found around the tobacco leaf. Tobacco is seasoned with benzene. Potassium tellurite is absorbed by plants. Benzene can enclose a metalloid in a fullerene. Tellurite is a sulfur metalloid that can take the place of the Reiske of mitochondrial respiration. Tellurite also causes cancer. I read that alpha synuclein was involved in Parkinsons, Alzheimers, and breast cancer. I think because of the colors, Alzheimers has to do with tellurite and Penicillium chrysognum, or another fungus, and Parkinsons has to do with Aspergillus fumigatus and Aspergillus terreus. Just a thought. - Sleblanc

I'm wondering what research is being done on the connection between nicotine and AD. I have read that smokers are more at risk for developing AD, but I have also read that the use of nicotine can have a positive effect on memory in persons with AD. My husband was a heavy smoker, and was forced to quit after he had a heart attack. While he was in the process of withdrawal, he came home from work in tears one day, saying "I can't do my job unless I smoke." His whole process of problem-solving was intimately connected with tobacco use - encounter a problem, sit down, have a cigarette, solve the problem. About a year after he had quit smoking, he began to develop memory problems. Now, he has been diagnosed with probable AD, and is on Aricept. He is only 62. Could nicotine have both the effect of improving cognition and imparing it - like a toggle switch. Or could nicotine somehow replace a naturally occuring chemical in the brain, which does not reactivate when people quit smoking? —Laura Sauter (threepenny@ap.net)

See Related Comments—Posted 15 September 2004
Ott A, Andersen K, Dewey ME, Letenneur L, Brayne C, Copeland JR, Dartigues JF, Kragh-Sorensen P, Lobo A, Martinez-Lage JM, Stijnen T, Hofman A, Launer LJ, . Effect of smoking on global cognitive function in nondemented elderly. Neurology. 2004 Mar 23;62(6):920-4. Abstract

Treatment-based Disovery

Folic Acid for Symptomatic Relief of “Sundowning” Syndrome—Posted 2 October 2009

I would like to share some anecdotal evidence of the benefit of folic acid for the relief of “sundowning” syndrome, often found in Alzheimer’s patients.

My mother, at age 82, moved into my home in September 1999. I had offered to take her in after she had walked out of her New Hampshire apartment at 10 p.m. in her nightgown, “looking for me.” There was no diagnosis of Alzheimer’s at the time, so I did not know what I was in for. I lived alone, 400 miles from my nearest relatives, and had no close friends on whom I would impose caregiver relief burdens.

A month later, in October 1999, she was diagnosed with Alzheimer’s. On December 1, 1999, she fell and suffered a broken shoulder and cracked pelvis, followed immediately by sciatica, shingles, and postherpetic neuralgia (PHN). After being virtually bed-bound for five months, she regained her mobility, thanks to Neurontin, and resumed moderate activity in April 2000.

During May 2000, she suddenly started the “sundowning” syndrome. At about 5 p.m. every afternoon, she would go to the front door to leave the house and take a (nonexistent) bus to go home to her mother. I foolishly spent hours explaining to her that her mother had died, that there was no bus, etc. This was while I was trying to prepare dinner, and it was very frustrating for me. Her activity and anger increased daily. I was resigned to taking her for a drive around the neighborhood each day for about 30 minutes to break the mental cycle, and when we returned home, she accepted that she was, indeed, home.

About four weeks after this sudden, continuous, and consistent “sundowning” behavior, I heard a radio program that recommended folic acid for Alzheimer’s. I started giving my mother a single non-prescription folic acid tablet (I believe they were 400 μg) at each meal and bedtime, for a total of about 1.6 mg per day. Within a few days, her “sundowning” completely disappeared. June was uneventful, and in July we moved to New Hampshire to be near my relatives so I could get relief from my 24/7 caregiving duties. My mother drove with me all night in a rental truck (she loved it!), and we moved into a small, two-bedroom apartment. The “sundowning” remained absent completely, even with brand-new surroundings.

In February 2001, we moved into a larger apartment across town, and again no “sundowning” occurred. During June 2001, she started the “sundowning” again in a mild form, and I increased her folic acid dose by about 50 percent—to six tablets a day (total 2.4 mg). Within a few days her “sundowning” ceased completely, and she stayed in this condition through a second fall, two strokes (one was a TIA), and incontinence during the remainder of 2001.

She entered a county nursing home in late December 2001, and passed away in March 2003. She had directed that her body be donated for medical research, and Boston University accepted her. After having to quit high school at age 16 to support her family during the Depression, she finally got to “go to college.”

I realize my (and my mother’s) experience is anecdotal in nature, but I am a trained engineer (BS, Stanford) and I majored in Quantitative Methods during my MBA program at UCLA. I was constantly “drawing a graph” in my mind while maintaining notes during this entire experience. I also noted on C-SPAN in about 2002 that the NIH was starting five new investigative protocols for Alzheimer’s, one of them involving folic acid.

I hope my information can be used in some investigative way, at least for symptomatic relief for Alzheimer’s patients. I survived my caregiving tenure only because of folic acid, in my opinion. I would never have been able to provide 24/7 care with “sundowning” every day.—Edward Rathje

Agitation and Alerting Agents—Posted 9 December 2004

A person witih cognitive difficulties is hyperactive, can't focus attention and is very difficult to manage. Sound familiar? No, I am not talking about adult attention deficit hyperactivity disorder. I am referring to a person with dementia complicated by agitation. Could alerting agents such as methyl phenidate or medafonil be helpful for this population? Has anyone tried this? Do chemical changes in the brain support this hypothesis?
—Henry Brodaty (h.brodaty@unsw.edu.au)

Gingko Biloba and Yerba Mate Tea—Posted 19 February 2004

This message is to inform you of my findings if you will lend me your eyes for a moment. My grandmother is in the early stages of Alzheimer's.

Several months ago, I began giving her one 50 mg. capsule of gingko biloba in the morning and one cup of yerba mate tea in the afternoon. My findings indicate a huge improvement.

For example, before the gingko and yerba mate, her sleep was erratic—up and down all day long. Now it's regular. Another example is repeating phrases over and over again: The gingko has all but stopped this. The yerba mate has evened out her sleeping habit to a normal level.

Take this as you wish. Perhaps if you tested this in a lab environment, you would see the same exciting finding I did: that the combination of these two herbs has been shown to reduce greatly the effects of early Alzheimer's.

Please feel free to contact me with any questions. I'm here to help also.—Michael Griffin. (sodapop@accessatc.net)

Last Saturday, she was especially anxious, and my father contacted the doctor, who prescribed her some pills to sleep that contain Zolpidem Hemitartrato, 10 mg. She took half a pill at 7:00 p.m.

What occurred next astonished us, because once my mother began to take that medicine, her behavior shifted significantly: She began to speak rationally, to remember things and names, to eat properly. In brief, she became a different person.

Yesterday, my father told the doctor what happened, but the doctor can¹t properly explain the reason for such a sudden change. I would like to ask Alzforum about the matter. Can you give me some rational explanation for this situation?

Sincerely,

Javier C.

Comment by Doug Galasko, University of California, San Diego

The story is curious, but difficult to interpret. Zolpidem is a very short-acting hypnotic (sleep-promoting) drug, similar in some ways to Valium. Although there are many possibilities, my guess is that the patient may have had worsening of behavior and attention due to agitation and delirium (possibly with visual hallucinations of seeing people who were not present), and that the Zolpidem provided a calming influence, which allowed the patient's attention to be refocused.

Unfortunately, this doesn't reveal a new treatment target in AD, but highlights the beneficial effects of looking for something reversible when a patient with Alzheimer's has a sudden behavioral change.

Comment by Tennore Ramesh, ALS Therapy Development Foundation

The drug Zolpidem binds to benzodiazepine receptors and is used as a sleeping pill. Interestingly, the benzodiazepine receptors are also currently being investigated in microglial activation, and ligand binding to this receptor is used as a candidate in imaging gliosis. The possibility of this drug inhibiting the damaging effects of microglia is interesting. For a review of this type of microglial imaging, see Cagnin et al., 2002 and Debruyne et al., 2003.

Q&A with Nuri Farber, Washington University School of Medicine, St. Louis, Missouri

Q: Hi Nuri. This query made me wonder whether this observation relates to the NMDA receptor hypofunction hypothesis of AD. Isn't Zolpidem a GABA agonist? If so, couldn't it compensate for the loss of GABA inhibition caused by NMDA receptor hypofunction (NRHypo)? Is it surprising to see such an acute effect in a patient? I always imagined that excitotoxic injury would be chronic and not reversible in such a short time frame, but perhaps I imagined incorrectly?

A: Yes, Zolpidem does work at GABA receptors. However, it acts only at a subgroup of them. Thus, you are correct in that it could compensate for some of the loss of GABAergic inhibition produced by NRHypo. The acute effect is not surprising if NRHypo was responsible for her symptoms. We hypothesize that there are two different processes that might underlie the cognitive and behavioral changes seen in AD. One arises directly from the disinhibition produced by NRHypo. Restoring inhibition would be expected to immediately reverse the observed changes. The second one arises from the physical injury to the neuron and the neuron no longer being able to function. This second process would not be expected to improve acutely, or maybe at all, from the restoration of inhibition. There is some experimental evidence to support the first process. The evidence involves treating normal human volunteers with an NMDA antagonist. Such treatment produces decrements in certain forms of learning. Adding an agent that reverses the disinhibition has been found to prevent the impairment in learning from occurring.

While this makes sense theoretically, I can't tell you if this is what went on in the person's brain. One of the issues is that there could be several non-AD processes that were occurring in the patient's brain and that Zolpidem treated such a condition. One would have needed to have evaluated the patient prior to her taking Zolpidem in order to have determined whether the symptoms were primarily from AD or some other process.

One problem with GABAergic agents is that they are sedative and impair memory on their own. Thus, it is usually tough getting an elderly patient to tolerate them without adversely affecting cognition. Zolpidem, because it hits just a subset of GABA receptors, might be better tolerated. Given how things on the Internet can take on a life of their own, my main concern is that somehow lay people will decide that their loved ones need to be placed on the miracle drug Zolpidem and seek out this unproven drug instead of going with a proven treatment.

Omega3 and Vitamin E—Posted 21 October 2002

Her physician keeps increasing the meds, so I gave my mother Omega3 from the DocsEssentials package along with Vitamin E since research states that the brains of Alzheimers patients are lacking this essential nutrient. We all have seen a remarkable difference in her cognitive skills and memory. I now have put her on the 6 synergystically blended vitamins and my mother is having less forgetful periods for longer periods of time. There are many Omega3 brands but cold pressed fish oil is the one recommended by research. —L. Melso

Editor's Note: L. Melso works in the marketing department for the DocsGuide, Inc. company.

Marijuana and AD—Posted 2 May 2001

Comment by June Kinoshita (junekino@alzforum.org) —Posted 3 May 2001

Thanks very much for your message. It is quite intriguing! I did a quick search of the PubMed database and found this article on a drug, dronabinol, which activates the cannabinoid (marijuana) receptor:

Volicer L, Stelly M, Morris J, McLaughlin J, Volicer BJ. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease. Int J Geriatr Psychiatry. 1997 Sep;12(9):913-9.

The study shows that the drug may help with appetite loss and agitation in some patients. A couple of other papers suggest that the cannabinoid receptor may help stimulate nerve growth factor, and also blocks the release of a brain chemical called glutamate, which can be toxic under certain circumstances. I'll do some further investigation. Thanks for sharing this very interesting story.

Comment by Ming Chen (michen@hsc.usf.edu)—Posted 11 May 2001

This family caregiver's account described the magic effects of marijuana that is accidentally given to an Alzheimer patient. In the mysterious and devastating world of Alzheimer's disease, we may need to keep an open mind to "crazy" ideas.

The mechanisms of action of several drugs of abuse (marijuana, amphetamine, heroin, etc.) are complicated, but they have a common effect in the brain: to stimulate neurotransmission either by blocking neurotransmitter reuptake, i.e., prolonging the transmitters' lifespan (1), or by enhancing neurotransmitter release (2-4). This may be why they produce euphoria, heightened sensory perception, illusion and paranoid psychosis - effects that normal people should not look for, but may be exactly what Alzheimer patients need.

These drugs have many adverse effects in the healthy brain. This is why they are illegal. However, several studies have shown that marijuana (cannabidiol) increases blood flow in the brain and has neuroprotective effects in cerebral ischemia injury (5-7). Similar effects have also been reported for amphetamine (8, 9).

Taken together, these findings should encourage the establishment of professionally managed, double-blind, and placebo-controlled clinical trials to test the validity and significance of these drugs in Alzheimer patients. Preliminary studies should also be carried out in current animal models or in some oldest-old animals that display natural memory impairments.

These drugs induce psychosis, hallucination, depersonalization, anxiety, panic, transient amnesia and myocardial infarction (1). However, the effects are highly dose-dependent and mostly in young people. Whether or not they will happen in the memory-impaired elderly remains a wide open question, but should be closely monitored. The therapeutic window between desired and undesired effects may be narrow, but should exist.

References

1. Craig, C.R. and Stitzel, R.E. Modern pharmacology. 5th edn. Little, Brown & Co., Inc. Boston 1997. Abstract Unavailable.

2. Chen JP, Paredes W, Li J, Smith D, Lowinson J, Gardner EL. Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis. Psychopharmacology (Berl). 1990; 102(2):156-62. Abstract

3. Shen M, Thayer SA. Delta9-tetrahydrocannabinol acts as a partial agonist to modulate glutamatergic synaptic transmission between rat hippocampal neurons in culture. Mol Pharmacol. 1999; 55(1):8-13. Abstract

4. Konradi C, Leveque JC, Hyman SE. Amphetamine and dopamine-induced immediate early gene expression in striatal neurons depends on postsynaptic NMDA receptors and calcium. J Neurosci 1996;16(13):4231-9. Abstract

5. Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A. 1998;95(14):8268-73. Abstract

6. Louw DF, Yang FW, Sutherland GR. The effect of delta-9-tetrahydrocannabinol on forebrain ischemia in rat. Brain Res. 2000; 857(1-2):183-7. Abstract

7. Nagayama T, Sinor AD, Simon RP, Chen J, Graham SH, Jin K, Greenberg DA. Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci. 1999; 19(8):2987-95. Abstract

8. Stroemer RP, Kent TA, Hulsebosch CE. Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats. Stroke 1998; 29(11):2381-93. Abstract

9. Maulik N, Wei Z, Liu X, Engelman RM, Rousou JA, Das DK. Improved postischemic ventricular functional recovery by amphetamine is linked with its ability to induce heat shock. Mol Cell Biochem 1994; 137(1):17-24. Abstract

Comment by Ming Chen (michen@hsc.usf.edu) —Posted 15 May 2001

The Supreme Court ruling today makes marijuana use in medicine more difficult. However, the court did not ban the clinical research. I read that the UK and Canada are currently doing clinical trials on it. Marijuana is known to play a beneficial role in many neurological disorders such as multiple sclerosis, glaucoma, epilepsy, insomnia, depression, Parkinson's, nausea and pain. But I haven't seen any systematic study of it in AD.

So it seems important to pass the caregiver's story around and to some powerful people who may come up with a solution. In a desperate disease like AD, we need to take any reasonable leads seriously - legal problems should not block the research especially on its available derivatives.

More References—Posted 21 October 2002

Molina-Holgado E, Vela JM, Arevalo-Martin A, Almazan G, Molina-Holgado F, Borrell J, Guaza C. Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J Neurosci. 2002 Nov 15;22(22):9742-53. Abstract

Grundy RI. The therapeutic potential of the cannabinoids in neuroprotection. Expert Opin Investig Drugs 2002 Oct;11(10):1365-74. Abstract

Cannabinoids protect against Amyloid-ß neurotoxicity—Posted 24 October 2002

The reports that cannabis may relieve some of the symptoms of Alzheimer's disease combined with studies demonstrating neuroprotective properties of cannabinoids all point to the potential benefits of these compounds. The Amyloid hypothesis of Alzheimer's disease suggests that the amyloid-β peptide is the toxin responsible for the neurodegenerative changes associated with the disease pathology. As part of a long running study to identify effective inhibitors of amyloid-ß neurotoxicity I have studied the effects of endogenous cannabinoids. In-text reference: [Milton NGN. Anandamide and noladin ether prevent neurotoxicity of the human amyloid-beta peptide. Neurosci Lett. 2002 Oct 31;332(2):127-30. Abstract

The results from this study demonstrated that the endogenous cannabinoids anandamide and noladin ether were effective at preventing the neurotoxicity of amyloid-ß in an in vitro Alzheimer's model. The mechanism of action involves cannabinoid CB1 receptor activation of a p42/p44 mitogen activated protein kinase pathway. The presence of this receptor type within the central nervous system and the ability of peripherally administered cannabinoids to act on these brain receptors all point to the potential for development of an Alzheimer's therapy using cannabinoids.

The observed neuroprotective properties of cannabinoids provide an explanation for the observations with obtained with cannabis use. However an important note of caution must be added. These neuroprotective properties are lost at high concentrations and indeed at concentrations above 100 µM I have demonstrated that anandamide increases the neurotoxicity of amyloid-ß. It is therefore clear that the development of any therapy will require either a cannabinoid devoid of neurotoxic activities or a carefully regulated therapy. As such I couldn't recommend cannabis use for Alzheimer's until appropriate trials have been carried out to establish whether it has beneficial or detrimental actions to the patients.

The interest in this work expressed by the general public (see news article) suggests that the Pharmaceutical Industry may wish to take note and consider the potential of the cannabinoid based compounds they are already developing for Multiple Sclerosis and other diseases.

With regards to the query ["What about short-term effects of cannabinoids reported by the person whose grandmother ate the brownies?"]: It is possible that cannabinoids could exert a quick action by preventing actions of amyloid-β on neurons. A paper by Dodart et al in Nature Neuroscience indicates that if you neutralise the amyloid-β with antibodies you can reduce very rapidly the memory deficits associated with overexpression of amyloid-β (Dodert et al., 2002). The speed of the effect suggests that amyloid-β has reversable actions on neurons which affect memory, if the cannabinoids themselves act to prevent these effects then this could explain the rapid response seen in the person who ate cannabis containing brownies.

Cannabinoids themselves would get to the brain relatively quickly after consuming the food and certainly would be able to exert rapid effects. I can see more and more work to get to the bottom of this in the lab. Hope this helps. The poster is being presented at the 3rd Neurobiology of Aging conference on the 31st October.-Dr Nathaniel Milton

Comment by June Kinoshita—Posted 11 August 2003

As evidence of growing interest in endocannabinoids among neurodegenerative disease researchers, check out the following paper: van der Stelt, M, Hansen, HH, Veldhuis, WB, Bär, PR, Nicolay, K, Veldink, GA, Vliegenthart, JF, Hansen, HS. "Biosynthesis of endocannabinoids and their modes of action in neurodegenerative diseases." Neurotox Res, 2003.

Abstract: Endocannabinoids are thought to function as retrograde messengers, which modulate neurotransmitter release by activating presynaptic cannabinoid receptors. Anandamide and 2-arachidonoylglycerol (2-AG) are the two best studied endogenous lipids which can act as endocannabinoids. Together with the proteins responsible for their biosynthesis, inactivation and the cannabinoid receptors, these lipids constitute the endocannabinoid system. This system is proposed to be involved in various neurodegenerative diseases such as Parkinson's and Huntington's diseases as well as Multiple Sclerosis. It has been demonstrated that the endocannabinoid system can protect neurons against glutamate excitotoxicity and acute neuronal damage in both in vitro and in vivo models. In this paper we review the data concerning the involvement of the endocannabinoid system in neurodegenerative diseases in which neuronal cell death may be elicited by excitotoxicity. We focus on the biosynthesis of endocannabinoids and on their modes of action in animal models of these neurodegenerative diseases.

See Related News Story: Cannabinoid Receptors and AD: Searching Beyond the Simple Story —Posted 7 March 2005

More References—Posted 16 December 2005

Ehrhart J, Obregon D, Mori T, Hou H, Sun N, Bai Y, Klein T, Fernandez F, Tan J, Shytle D. Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation. J Neuroinflammation. 2005 Dec 12 ; 2(1):29. Abstract

More References—Posted 17 May 2006

Tagliaferro P, Javier Ramos A, Onaivi ES, Evrard SG, Lujilde J, Brusco Neuronal cytoskeleton and synaptic densities are altered after a chronic treatment with the cannabinoid receptor agonist WIN 55,212-2. J Brain Res. 2006 Mar 24. Abstract

More References—Posted 22 December 2006

Eubanks LM, Rogers CJ, Iv AE, Koob GF, Olson AJ, Dickerson TJ, Janda KD. A Molecular Link between the Active Component of Marijuana and Alzheimer's Disease Pathology. Mol Pharm. 2006 Dec 4;3(6):773-777. Abstract

More References—Posted 28 June 2007

Marchalant Y, Cerbai F, Brothers HM, Wenk GL. Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats. Neurobiol Aging. 2007 Jun 8. Abstract

Turmeric and Alzheimer's—Posted 14 December 2001

With reference to two research findings about the reduction of risk of Alzheimer's.

1. UCLA study Turmeric indicates that turmeric consumption reduces risk of Alzheimer. Evidence is also hinted to by the lowest rate of Alzheimer's in a certain village in India and low rates in India in general.

2. University of New York indicates that vigourous physical activity between age of 20 to 60 reduces risk of Alzheimer.

These indications are based entirely on statistical analysis and none at all on molecular analysis. Inexperienced medical statisticians have a tendency to overlook translational dependencies in statistics.

In either of these cases of statistical studies, has anyone ever correlated the fact that both activities of curry ingestion and physical exertion induces the subject to consume lots of water and fruit juice? I could therefore induce a hypothesis that high intake of water and fruit extracts reduces the risk of Alzheimer's. Could someone run a correlation on this, please?

Thank you.—Syloke Soong (syloke.soong@nsc.com)

Vitamin C IV—Posted 3 January 2008

My husband was diagnosed with early Alzheimer's in his early forties some 20 years after receiving a diagnosis of having a mild case of multiple sclerosis. In retrospect, I believe many of his symptoms were more of Alzheimer's than MS. He died at 49 from complications of the diseases. He was a physician, an orthopedist and physiatrist. I am an attorney.

In a desperate attempt to toll the effects of what we thought were MS in 1989, he had an expensive experimental procedure performed in San Diego where we were living to have the amalgam fillings removed from his teeth. The dentist handling the procedure took 2 days (almost 7 hours each day), and during the entire process, my husband received a vitamin C IV to remove any residual mercury from the body through the urine, though I do not know more about the procedure. I believe it is called "chelation."

I cannot impress upon you the complete but temporary improvement and resolve of his mental state, acuity and the immediate return of his sharp, quick wit and personality (lasting 3-4 days) that I observed at the end of each day of the procedure. This improvement seemed to last a couple of days. He was back to his old self—sharp, charming, quick-thinking, engaging everyone in a room, relating to each personally and positively for extended times. It was miraculous, and since that time, I have mentioned the experience to many neurologists I have come to meet, suggesting there is an answer for a cure in the vitamin C IV, but to date, I've not heard of anyone acting on it.

I am begging you to at least look into it. It would not take much to take a couple of Alzheimer's patients, let them lie comfortably in a dentist chair for a few hours relaxing, on a vitamin C IV and observe the change in mental state at the end of the day. Perhaps the removal of the amalgam had something to do with his reaction as well, but again, the improvements were short-lived, which makes me think it was the vitamin C IV.

After watching a PBS special on Alzheimer's today, it brought back the recollection of the wonders of the vitamin C IV, and it is Dr. Brad Hyman's research into prophylactic procedures that I thought might be most interesting in this experience.

Thank you for taking the time to read this. If there is a chance that this could help someone, that would be wonderful!—Kimberly Hysni

Links between Alzheimer's and Other Major Diseases

Alzheimer's and Lyme Disease—Posted 29 March 2007
I am a Lyme disease patient and activist. The newest article about Alzheimer's and perhaps having a new test for it is being circulated on the private doctor's message forum I am on. The discussion has been centered on studies, such as Alzheimer's—A Spirochetosis? by Judith Miklossy. Dr. Miklossy's study showed that autopsies on 14 Alzheimer's brains presented brains riddled with spirochetes, including the Lyme spirochete. It is thought that it is these microbes which may be causing the inflammation and plaques. It would make more sense to me to look for the cause of the inflammation so it can be eliminated instead of looking for a drug which would only dampen the inflammation and leave the cause of the inflammation active and thriving.

I had an experience with my father-in-law that I would like to share. It's not proof of anything, but it's an example of the confusion that occurs with these diagnoses. My father-in-law (FIL) slowly began to get symptoms such as memory loss (he was about 85 at the time), urinary incontinence, and a shuffling gait. I brought up the issue of Lyme to my husband's family, but because he had no arthritic symptoms or fevers they just assumed that Lyme wasn't a factor. He progressively worsened, and although everyone chalked it up to Alzheimer's, I was still skeptical. I finally talked the family into bringing him to my Lyme doctor. I had seen a show on television about normal pressure hydrocephalus (NPH) and knew the symptoms were those of my FIL's. My Lyme doctor said she would order an MRI to see if NPH was the problem. As we were about to leave, I asked her if she ordered a Lyme test, and she said no she hadn't and didn't think that Lyme was involved (even though my FIL was an avid gardener all his life) but that it couldn't hurt, so he was also tested for Lyme.

A few days later she called me and not only did he have NPH, but he also had the highest Lyme titers she had ever seen. Medicare allowed him to have 1 month of IV antibiotics, and we had to drive him each day (a 2-hour drive altogether) to the hospital for his IV. About 2 weeks into treatment he began to improve. He could pick up his feet and get up out of chairs much more easily. His memory improved a bit. When they took him off the IV, he went rapidly downhill. The Lyme doctor only gave him a low dose of amoxicillin, which is really not effective for late-stage Lyme. A couple of weeks later he couldn't stand up, so an ambulance came and took him to the hospital. He was a bit ornery so they gave him drugs to calm him down. I didn't make a big deal of it at the time because I didn't know what I know now, but I think it must have been Haldol or something similar. He became incoherent and a vegetable, but we chalked it up to his worsening condition. He was constantly performing repetitive, meaningless motions and looked like he was trying to communicate but couldn't.

One day my husband went in to visit, and his father was back to his previous state before he entered the hospital. He wondered why he was in the hospital and why we had left him there. I think they must have forgotten a dose of whatever drug he was on. The next day he was back to being a vegetable. Then he couldn't swallow. I didn't know it at the time, but Haldol, for one, is a drug which can cause inability to swallow. So, they gave us a choice of tube feeding him and letting him be a vegetable or letting him starve to death. Due to their prognosis we decided that the feeding tube would not accomplish anything in the long run. If I had known what I know now, I would have demanded that they take him off the medication. It took him 3 weeks to starve to death in hospice. I am wondering how many old people this has happened to and is continuing to happen to. I've heard other stories.

So, I guess the point I am trying to make is this: in some or many cases, NPH and Alzheimer's are being confused with each other and also that Lyme could possibly cause both conditions. Being involved with Lyme politics, I am beginning to see that treatments that don't address the primary cause of these illnesses are the ones being invented and pushed: symptomatic treatments instead of curative ones. We are not being allowed to have long-term antibiotic treatment (as is needed in syphilis, Lyme's close cousin). Drug companies do not want to find microbes as the cause or cofactors of many of these illnesses because treating these primary causes may get the people well, or at least functional, and then all the symptomatic treatments will not be needed. Many symptomatic treatments equal profits. We have so few Lyme-literate doctors to begin with, and systematically they are being investigated and having their licenses revoked. This is a criminal and very critical situation concerning the health of our nation.

AD and MS, CFS and Atheroscleorisis—Posted 26 July 2002
By Paula Carnes

I have a diagnosis of chronic fatigue syndrome, but I also have an intracellular infection of mycoplasma fermentans (incognitus strain.) This infection was discovered in peripheral blood by PCR at Immunoscience Labs in Beverly Hills, CA. I have read research that implicates intracellular infections of c. pneumoniae and several mycoplasmas as underlying causes of MS, CFS and atheroscleorsis. I am so pleased to see this research article now showing a POSSIBLE link to Alzheimers. It is a real possibility that we may be able to get these horrible diseases under control with increased devolopment and judicial use of appropriate antibiotics such as azithromycins, minocycline, floxacins, etc. I think it is time we stopped using the antibiotics on cows and chickens and started treating human beings aggressively for these infections.

Stereotactical Phenomenon in TBI Biomechanics—Posted 31 July 2001
By Catalin Obreja

Stereotactical Phenomenon in TBI Biomechanics could explain the correlation between the Traumatic Brain Injury (TBI) and Alzheimer’s disease (AD). Different epidemiological studies showed that the traumatic brain injuries (TBI) are correlated with higher incidence and earlier onset of Alzheimer's disease (AD), particularly when associated with APOE epsilon 4 allele and when the loss of consiousness exceeds five minutes. Thus, the TBI is probably one of the main environmental factors in the AD pathogenesis. See More

AD and Vascular Dementia Connection—Posted 4 June 2001

In AD research, so many transgenic models make things clearer than before. I wonder which model will help clarify the relationship between AD and VAD? In other words, is there a model that can help find the vascular dysfunction in AD? —Ajunxj Panther ajunxj@hotmail.com

Alzheimer's and Schizophrenia—Posted 28 March 2001

I wanted to pass along a comment that Peter Davies made to me recently. He observed that the brains of people with schizophrenia have never been reported to show any Alzheimer pathology. We wondered whether there is something about schizophrenia that inteferes with the molecular mechanisms of AD, or, perhaps more likely, whether antipsychotic medications may prevent the development of AD pathology. I'd be interested in hearing from researchers who have studied the neuropathology of schizophrenia to find out whether this observation is robust. I'd also be curious to know whether anyone has studied antipsychotic medications in AD-relevant assays or looked at their effects on gene expression in neuronal cultures. —June Kinoshita junekino@alzforum.org

Comment by Ming Chen—Posted 26 April 2001

Dr. Peter Davies has raised an important question of why schizophrenia patients do not develop AD in their late years. Here I propose a "reserve-loss" model to explain it.

Take osteoporosis for instance. The elderly commonly will have bone loss, but why will some of them develop into clinical osteoporosis? It may depend on two major factors: exercise and reserve. The role of exercise is clear but reserve is also important (i.e., how much you start with). According to this model, those who have strong bones at young age (like Mike Tyson) will have much lower risk of osteoporosis or muscle atrophy at old age than average people.

Schizophrenia (paranoid) is characterized by overly active brain function, so some of the patients are highly creative at one time, but can also be paranoiac or "crazy thinking" at others (note that van Gogh, Picasso and Einstein are considered as mild schizophrenics by some). Because their brains are more active (like Tyson's bones and muscles) - or more "brain reserve" to start with - they will be expected to have a much lower risk of AD than average people during aging when synapse weakening/loss will occur (like bone loss or muscle weakening).

This model can also explain why education and brain exercises are protective factors against AD. Experimentally, the model may be tested by its predictions: if schizophrenia and AD are inversely related, then drugs that can induce paranoid psychosis in humans (such as amphetamine, which acts by stimulating neurotransmission) may be able to ameliorate AD conditions. On the other hand, antipsychotic drugs (such as chlorpromazine which inhibits neurotransmission) may induce AD-like conditions in old animals.

Indeed, some of these experiments have been done (1, 2) and similar ideas discussed (3, 4). —Ming Chen michen@hsc.usf.edu

References

1. Wisniewski HM, Constantinidis J, Wegiel J, Bobinski M, Tarnawski M. Neurofibrillary pathology in brains of elderly schizophrenics treated with neuroleptics. Alzheimer Dis Assoc Disord. 1994 Jan 1;8(4):211-27. Abstract

2. Gong CX, Shaikh S, Grundke-Iqbal I, Iqbal K. Inhibition of protein phosphatase-2B (calcineurin) activity towards Alzheimer abnormally phosphorylated tau by neuroleptics. Brain Res. 1996 Nov 25;741(1-2):95-102. Abstract

3. Etienne P, Baudry M. Calcium dependent aspects of synaptic plasticity, excitatory amino acid neurotransmission, brain aging and schizophrenia: a unifying hypothesis. Neurobiol Aging. 1987 Jul-Aug ;8(4):362-6. Abstract

4. Chen M. The Alzheimer's plaques, tangles and memory deficits may have a common origin. Part III: animal model. Front Biosci. 1998 Jun 17;3:A47-51. Abstract

References contributed by Peter Davies—Posted 24 May 2001

Arnold SE, Trojanowski JQ, Gur RE, Blackwell P, Han LY, Choi C. Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry. 1998 Mar 1;55(3):225-32. Abstract

Purohit DP, Perl DP, Haroutunian V, Powchik P, Davidson M, Davis KL. Alzheimer disease and related neurodegenerative diseases in elderly patients with schizophrenia: a postmortem neuropathologic study of 100 cases. Arch Gen Psychiatry. 1998 Mar 1;55(3):205-11. Abstract

Comment by Ben Oken—Posted 20 June 2001

I must disagree with your assertion of lack of comorbidity of Alzheimers disease and schizophrenia. Please see following references for counterexamples: —Bob Oken robertoken@nac.net

Oken RJ and McGeer PL. Schizophrenia, Alzheimer's Disease, and Anti-inflammatory Agents. Schizophr Bull. 1996 Jan 1;22(1):1-4. Abstract

Bayer TA, Havas L, Falkai P. Evidence for activation of microglia in patients with psychiatric illnesses. Neurosci Lett. 1999 Aug 20;271(2):126-8. Abstract

Comment by Peter Davies —Posted 6 July 2001

I don't see anything in the references given that suggests that AD pathology - neuritic plaques and neurofibrillary tangles in BOTH hippocampus and neocortex - occur with any substantial frequency in elderly patients with schizophrenia. The Bayer reference finds microglial activation in 3 of 14 schizophrenics, but the ages of the individual patients was not given. HLA-DR reactivity is certainly not a reliable indicator of AD pathology (1).

My point is solely concerned with the pathologic hallmarks of AD: I am not arguing that elderly schizophrenics do not show signs of cognitive impairment: many appear to do so (2). However, I am not aware of post mortem studies of a substantial series of elderly schizophrenics that fails to show lower frequency of AD lesions than in the general population.

1. Mattiace LA, Davies P, Dickson DW. Detection of HLA-DR on microglia in the human brain is a function of both clinical and technical factors. Am J Pathol. 1990 May 1;136(5):1101-14. Abstract

2. Powchik P, Davidson M, Nemeroff CB, Haroutunian V, Purohit D, Losonczy M, Bissette G, Perl D, Ghanbari H, Miller B. Alzheimer's-disease-related protein in geriatric schizophrenic patients with cognitive impairment. Am J Psychiatry. 1993 Nov 1;150(11):1726-7. Abstract

Comment by Ratan Bhat —Posted 25 July 2001

I was reading your comment on Peter Davies's observation with interest - that the brains of people with schizophrenia have never been reported to show any Alzheimer pathology. If this is true, I would like to suggest a common molecular target having opposing expression patterns between the two neuronal disorders. As you know the Ser/Thr kinase GSK3b has been implicated in the tau pathology of AD. Both, levels of GSK3b and the active site phsophorylation have been shown to be increased in AD brain (pre-tangles and tangles) by Kahlid Iqbal and Richard Cowburn's groups.

Furthermore, Jesus Avila's group has recently demonstrated that inducible GSK3b adult transgenic mice develop pre-tangle pathology and neuronal degeneration. In contrast to AD, GSK3b immunoreactivity is decreased in schizophrenic brains. It is unclear whether or not this results in schizophrenia or is a unique developmental effect. However, since GSK3b is low in schizopheric brain tissue but is increased in AD brain, it raises the intriguing possibility that GSK3b or its signalling partners could be a common interfering molecular mechanism between AD and schizophrenia.

References:

Pei JJ, Tanaka T, Tung YC, Braak E, Iqbal K, Grundke-Iqbal I. Distribution, levels, and activity of glycogen synthase kinase-3 in the Alzheimer disease brain. J Neuropathol Exp Neurol. 1997 Jan;56(1):70-8. Abstract

Pei JJ, Braak E, Braak H, Grundke-Iqbal I, Iqbal K, Winblad B, Cowburn RF. Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes. J Neuropathol Exp Neurol. 1999 Sep 1;58(9):1010-9. Abstract

Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R, Avila J. Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J. 2001 Jan 15;20(1-2):27-39. Abstract

Beasley C, Cotter D, Khan N, Pollard C, Sheppard P, Varndell I, Lovestone S, Anderton B, Everall I. Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia. Neurosci Lett. 2001 Apr 20;302(2-3):117-20. Abstract

Kozlovsky N, Belmaker RH, Agam G. Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients. Am J Psychiatry. 2000 May 1;157(5):831-3. Abstract

—Ratan Bhat, Ph.D

Other Roles of AβPP, Presenilin and Aβ Peptide

Presenilin Hypothesis—Posted 2 May 2010
By Miguel Rodríguez-Manotas

The presenilin hypothesis should be explained taken into account the latest findings from the three-dimensional structure of secretase complex and the monomeric condition (Li et al., 2009).

If the water channels were, in fact, two distinct channels through which the same molecule of APP, in addition to water, could access the active site of the complex but suffering different strain, it probably will result in different products, as outlined in the model of progressive proteolysis of Ihara. This would agree with the monomeric condition.

It is easy to reach this conclusion through mathematical kinetic equations.

With this in mind presenilin would act on the APP as a high pass filter where probably Aβ42, in a suitable concentration range, were not a harmful substance but part (C49,...) of a modeling system of the brain.

View the mathematical proof [.pdf] of this hypothesis.

Comment by Juan Cabezas-Herrera—Posted 18 May 2010

Watanabe et al. (1), by intra-molecular complementation assays, revealed that transmembrane domain 3 (TMD3) of presenilin-1 (PS1) should play a role in the acquisition of proper proteolytic activity. Only the wt NTF/wt CTF and the TMD3mt/wt CTF combinations are able to express γ-secretase activity, both producing Aβ40 and Aβ42. At first glance, it may seem that the role of TMD3 is not fundamental since an irrelevant polypeptide (swap of TMD3) does not abolish the ability to produce Aβ or AICD. Intriguingly, TMD3mt/wt CTF showed a significant decrease in the production of Aβ40 and a notable increase in that of Aβ42.

This would support the hypothesis by Miguel Rodríguez-Manotas (Presenilin Hypothesis, posted 2 May 2010) about the possibility that the two water channels, which appear in the solved structure of 12 Å (2), are different gates to substrate access to the γ-secretase active site. Thus, the proteolytic mechanism in which longer Aβ species are generated can be explained by different substrate topological positions relative to the substrate gate, a hypothesis compatible with the progressive proteolysis model proposed by Ihara et al. (3) The native γ-secretase, and also the wt NTF/wt CTF combination, will produce more Aβ40 fragments because the processing of substrate is easier when the substrate enters through the "normal" channel. Conformational changes in γ-secretase caused by mutation in the TMD3, as well as in TMD3mt/wt CTF, would shift substrate and product trafficking through this alternative gate.

References:
1. Watanabe N, Takagi S, Tominaga A, Tomita T, Iwatsubo T. Functional analysis of the transmembrane domains of presenilin 1: Participation of transmembrane domains 2 and 6 in the formation of initial substrate-binding site of {gamma}-secretase. J Biol Chem. 2010 Apr 23. Abstract

2. Osenkowski P, Li H, Ye W, Li D, Aeschbach L, Fraering PC, Wolfe MS, Selkoe DJ, Li H. Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution. J Mol Biol. 2009 Jan 16;385(2):642-52. Abstract

3. Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Dolios G, Hirotani N, Horikoshi Y, Kametani F, Maeda M, Saido TC, Wang R, Ihara Y. Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase. J Neurosci. 2005 Jan 12;25(2):436-45. Abstract

First, consider the two forms of APP. The membrane AβPP form has a receptor-like protease(1) with a cytoplasmic region capable of binding small G-proteins.(2) In neurons, the membrane form is found at the synaptic zone at the tip of growth.(3,4) The secreted form of APP is an extracellular protease that has been shown to stimulate neurite extension.

Now consider that AβPP is also known as protease nexin II, a serine protease.(5,6,7) The serine protease inhibitor neuroserpin has been shown in PC12 cells not only to decrease the length of neural axon extensions, but also to stop axon growth altogether.(11)

I propose that the biological function of APP appears to be to act as a serine protease to "switch" neurons into the growth mode.

To weigh this idea, discoveries in other cell types should be considered: Maspins are serine protease inhibitors that insert into the membrane and control the cytoskeleton; without maspins, breast cancer cells metastasize.(8)

Next, consider that P53 turns on maspin expression by binding DNA.(9) Note that p53 binding is also required for bcl-2 expression. In neurons, AβPP seems to prevent p53 from binding to DNA.(10) So serpins and serine proteases have opposite relationships with P53. This makes sense because p53 binding protects quiescent neurons from apoptosis via bcl-2, while rapidly growing neurons could be easily eliminated if needed.(14)

Neuroserpins and α-1-antichymotrypsin (α-1-ACT) are serine protease inhibitors that could be acting as maspins. Interestingly, expression of APP and α-1-ACT have been shown to coexist together in the membrane of human skeletal muscle.(12)—a serine protease receptor with a serine protease inhibitor receptor.

Putting it all together, there seem to be two critical states of neurons: those that are growing and using serine proteases to do so, and those that are quiescent. Growing neurons would be using APP pathways, possibly through RhoG (a small G-protein) to extend microtubules, whereas quiescent neurons would use the membrane serpin. I speculate that serpins may act through RhoA to dictate a non-growth cytoskeletal structure.(13)

APP and Cholesterol

Another nice feature of this proposed APP function as a controller of "growth of non-growth" is that it explains the cholesterol relationship. The elongated membrane of the nerve growth cone would require more cholesterol in the membrane for structural stability. Simple membrane structures require less cholesterol, while complex membrane structures require more. The addition of cholesterol to membranes stabilizes the lipids, thus preventing them from floating away.(15) If the body wanted to get rid of cholesterol, it might attempt to use as much as possible in complex membranes like those of growing axons and growth cones.

For example, treating APP-transfected HEK cells with statin drugs reduced the processing of newly synthesized APP. Adding cholesterol to the HEK cells increased BACE cleavage of APP by fourfold.(16) The cells appear to choose the APP pathway in order to use cholesterol in the membrane!

What about the decrease of the α-secretase processing of APP? My understanding is that there are two main types of APP cleavage, α and β. Transgenic mice overexpressing APP when exposed to high cholesterol show an increase of the β-secretase cleavage of APP and a decrease of α-secretase cleavage.(17) Since α-secretase cleavage occurs at the membrane surface of neurons,(18) I suggest that this α cleavage might be an "off cleavage." Could it also be that neuroserpin inhibits APP, then the secretase cleaves it, turning the growth mode of the APP receptor off permanently, then stimulating the nerves nearby as if to take turns growing?

I reason that high cholesterol would push neurons into the APP cytoskeleton growing mode, which uses cholesterol in the membrane. Problems could occur once the neuron could no longer keep up the growing pace, or too much Aβ was made due to high cholesterol stimulating APP production. If the nerve became stuck in the growth mode, it makes sense that proteins used in growth could pile up; this includes APP, tau,(21) and α-synuclein as a plasma membrane omega fatty acid transporter.(22)

APP and Dementia

Another appealing feature of APP functioning as a serine protease and the neuron switching into a growth mode is that it might also help explain dementia and the neuron's mitochondria. Assuming that the mitochondria must be coordinated with neuron growth and division, it is interesting to note that the transmembrane protease called rhomboid responsible for the proteolysis of mitochondrial membranes is a serine protease.(19) So a serine protease in mitochondrial membranes appears to remodel the mitochondria from the mesh system into "portable, hotdog-like" organelles. I am suggesting that when APP, a plasma membrane serine protease receptor, switches the neuron to a growth mode, somehow a serine protease in the mitochondrial membrane is also switched on.

Where does this line of thought lead? Mitochondria have been called the "memory" of neurons, as they use their calcium stores to record stimulation and adjust neurotransmitter release based on stimulation.(20) Wouldn't it be interesting if the morphology of the mitochondria affected this calcium memory property? For instance, if the mitochondria are in the mesh form, the neuron can "remember," but when mitochondria are in the hot dog form during serine protease expression, the neuron cannot. This is, in effect, a speculation that sudden returnable memory relates to the state of the mitochondria. It is unknown whether the APP serine protease in the plasma membrane is coordinated with the mitochondrial serine protease, but the fact that they are both transmembrane serine proteases is suggestive. Could APP trigger dementia by causing the mitochondrial serine protease to be expressed?

Consider resveratrol, the polyphenolic compound of red wine, cranberries, and blueberries. Resveratrol has been found to slow the growth of prostate cancer cells.(23) Serine protease inhibitors—the serpins—use their phenol groups to inhibit the serine proteases. Could the return of memory that occurs with blueberries and other resveratrol-containing foods actually be due to resveratrol acting like a serpin, thus inhibiting the serine protease of the mitochondria and allowing the mitochondria to form back into a mesh?

There are a lot of possibilities with this growth model of APP as a serine protease. I hope enterprising scientists will take up testing it! —Angela Biggs, Independent Researcher.

Please note: Just in case it is not mentioned in the live discussion, I would like to note that clioquinol is an antifungal and it is not entirely understood how it is working in Alzheimer's patients.

References:
1. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19-25;325(6106):733-6. Abstract

2. Nishimoto I, Okamoto T, Matsuura Y, Takahashi S, Okamoto T, Murayama Y, Ogata E. Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o) Nature. 1993 Mar 4;362(6415):75-9. Abstract

3. Schubert D. The possible role of adhesion in synaptic modification. Trends Neurosci. 1991 Apr;14(4):127-30. Review. No abstract available. Abstract

4. Levitan and Kaczmarek. 1991. The Neuron. pp 343-344.

5. Qiu WQ, Ferreira A, Miller C, Koo EH, Selkoe DJ. Cell-surface beta-amyloid precursor protein stimulates neurite outgrowth of hippocampal neurons in an isoform-dependent manner. J Neurosci. 1995 Mar;15(3 Pt 2):2157-67. Abstract

6. Jin LW, Ninomiya H, Roch JM, Schubert D, Masliah E, Otero DA, Saitoh T. Peptides containing the RERMS sequence of amyloid beta/A4 protein precursor bind cell surface and promote neurite extension. J Neurosci. 1994 Sep;14(9):5461-70. Abstract

7. Oltersdorf T, Fritz LC, Schenk DB, Lieberburg I, Johnson-Wood KL, Beattie EC, Ward PJ, Blacher RW, Dovey HF, Sinha S. The secreted form of the Alzheimer's amyloid precursor protein with the Kunitz domain is protease nexin-II. Nature. 1989 Sep 14;341(6238):144-7. Abstract

8. Sheng S, Carey J, Seftor EA, Dias L, Hendrix MJ, Sager R. Maspin acts at the cell membrane to inhibit invasion and motility of mammary and prostatic cancer cells. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11669-74. Abstract

9. Zou Z, Gao C, Nagaich AK, Connell T, Saito S, Moul JW, Seth P, Appella E, Srivastava S. p53 regulates the expression of the tumor suppressor gene maspin. J Biol Chem. 2000 Mar 3;275(9):6051-4. Abstract

10. Xu X, Yang D, Wyss-Coray T, Yan J, Gan L, Sun Y, Mucke L. Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis. Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7547-52. Abstract

11. Parmar PK, Coates LC, Pearson JF, Hill RM, Birch NP. Neuroserpin regulates neurite outgrowth in nerve growth factor-treated PC12 cells. J Neurochem. 2002 Sep;82(6):1406-15. Abstract

12. Akaaboune M, Ma J, Festoff BW, Greenberg BD, Hantai D. Neurotrophic regulation of mouse muscle beta-amyloid protein precursor and alpha 1-antichymotrypsin as revealed by axotomy. J Neurobiol. 1994 May;25(5):503-14. Abstract and Akaaboune M, Verdiere-Sahuque M, Lachkar S, Festoff BW, Hantai D. Serine proteinase inhibitors in human skeletal muscle: expression of beta-amyloid protein precursor and alpha 1-antichymotrypsin in vivo and during myogenesis in vitro. J Cell Physiol. 1995 Dec;165(3):503-11. Abstract

13. Vignal E, Blangy A, Martin M, Gauthier-Rouviere C, Fort P. Kinectin is a key effector of RhoG microtubule-dependent cellular activity. Mol Cell Biol. 2001 Dec;21(23):8022-34. Abstract

14. Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis - the p53 network. J Cell Sci. 2003 Oct 15;116(Pt 20):4077-85. Abstract

15. Alberts et al. 1989. Molecular Biology of the Cell, 2nd edition. pp 279.

16. Frears ER, Stephens DJ, Walters CE, Davies H, Austen BM. The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport. 1999 Jun 3;10(8):1699-705. Abstract

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22. Pro Natl. Acad Sci USA 98 (16):9110-5.

23. Mitchell SH, Zhu W, Young CY. Resveratrol inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Cancer Res. 1999 Dec 1;59(23):5892-5. Abstract

Comment by Barry W. Festoff—Posted 19 December 2004

Angela Biggs refers to the protease nexin II form of AbetaAPP as a serine protease. Although her discussion and hypotheses are quite interesting, this is incorrect. It is a serine protease inhibitor, and not of the serpin class as originally conceived of by Dennis Cunnigham's group at UC, Irvine.

It is in fact a kunin-type serine protease inhibitor, actually a bikunin.

Comment by Angela Biggs—Posted 18 April 2005

Before we start dividing serine protease inhibitors up into groups we should look at the serine protease inhibitor family. Consider that they have been conserved in evolution and exist in not only eukaryotes but prokaryotes, thus they must serve a very important purpose. I am suggesting that serine protease inhibitors/ serine proteases are growth keys and thus a critical step in the evolution of single cells. I am merely suggesting a short cut by looking at the "big picture," the entire family of serine protease inhibitors, we may be enlightened and see the function of individual family members. See: http://mbe.oupjournals.org/cgi/reprint/19/11/1881

Comment by Ole Isacson—Posted 18 June 2005

I am pleased to find a posting by Angela Biggs with some reference to the synaptic-dendritic growth regulation hypothesis. The idea of a continuous dynamic growth-regulation disturbance (as a pathological synaptic mechanism) as the degenerative process in AD and Down syndrome is interesting. We started to investigate this hypothesis in vivo a few years ago by evaluating clues about growth-dynamics of the cholinergic synapse in hippocampus—and could clearly show a number of interactions that suggest that the APPs and Aβ regulation partly depend on normal cholinergic receptor function and trophic factor (e.g., NGF) regulation (Isacson et al., 2002). In this perspective, normal physiological actions of APP, growth factors, and transmitters can be viewed as highly interactive to produce the maximal synaptic efficiency—while altered genetic, environmental, or cellular problems may slightly shift such homeostatic mechanisms toward a vicious cycle of increased Aβ accumulation, synaptic dysfunction, and finally cell degeneration (Isacson et al., TINS 2002). While I have not thought of it strictly in terms of proteases, as highlighted by Angela Biggs, the overall "growth-dynamic" hypothesis can explain how a number of factors combined with age may generate the AD pathology as a common disease in a large number of people, and by many routes. See Alzheimer's disease and Down's syndrome: roles of APP, trophic factors and ACh. Isacson et al., 2002. Download pdf file.—Ole Isacson

Novel enzyme involved in Ab vaccine action?—Posted 28 December 2000

All the researchers in AD are now astonished by the Ab vaccine. Although extremely simple, it highlights a new way to overcome the disease. However, I am still puzzled by the mechanism by which the vaccine works. I have the idea that since the microglia are activated after vaccination, why does it not phage and diminish the plaque in normal condition, and what kinds of pathway (a new enzyme?) is involved in its action? If a new enzyme actually expressed, can we find it using classical biochemistry or by DD-PCR to find its cDNAand thus get its sequence? —Li Shupeng" <lishupeng76@hotmail.com>

Presenilins and transglutaminase regulation

Has anyone thought about a link between presenilins and "tissue" transglutaminase regulation? Any research in this area ?(I havn't found any yet!) Do researchers think this may be possible?
—Sebastien Hebert, graduate student <sehebert@hotmail.com>

Amyloidb peptide as infectious agent, analogous to prion?—Posted 19 October 2000

Karen Duff suggested I contact you about whether AlzForum is looking into the longshot possibility that there is something infectious about bamyloid. Karen said that there's been some talk lately about the deaths of both Henry Wisniewski and George Glenner from amyloidosis. I know the conventional wisdom goes strongly against any possibility of this being more than a coincidence, but was wondering if there's any discussion of the issue.

Best, David Shenk

Comment from June Kinoshita:—Posted 20 October 2000

I believe Stanley Prusiner has made such a suggestion.

Investigation of the role of APP during cell transformation

The mechanism by which mutant p53 gene causes cell transformation is unclear. In order to identify genes whose expression is altered in the course of cell transformation, the p53 overexpresser R6/#13-8 cell line and its spontaneous transformant R6#13-8/T2 were used to differentially display their mRNA. One clone that was down-regulated in transformed R6#13-8/T2 was identified. Sequencing analysis demonstrated that this clone was 98% identical to rat amyloid precursor protein (APP) gene. Mutations in APP are known to cause early-onset, autosomal dominant Alzheimer's disease. Moreover, some findings suggest that APP may play an important role in cognitive processes and cell death either by necrosis or by apoptosis; however, the normal cellular function of APP remains unclear. We report here the role of APP during cell transformation. Our research focuses on whether APP is directly involved in cell transformation in the presence or absence of mutant p53. A 1.1-kb fragment from the 3'end of the APP gene was obtained by reverse transcription-polymerase chain reaction (RT-PCR). An antisense APP gene was transduced into Rat6 embryo fibroblast cells via a retroviral vector carrying the neomycin-resistance gene. Six clones (R6/AS-APP#4, #6, #7, #8, #9 and #10) were obtained in neomycin-containing medium. One clone, R6/AS-APP#8, shared similar morphology with transformed cells in normal culture (DMEM/10% FBS). To investigate the transformability of R6/AS-APP#8 cells, a soft agar assay was performed. Expression of the APP gene in R6/AS-APP#8 is under study. Results will demonstrate the role of APP during cell transformation. We are now transducing the antisense APP gene into R6/#13-8 cells, with the aim of revealing the relationship between expression of APP and transformation of R6/13-8 cells with mutant p53. —Zou Quan <zou@public1.tpt.tj.cn>

Alzheimer's and Asthma Link

Is it possible that there is a connection between the rising incidence of asthma and Alzheimer's disease? The surfactants in the lung are the same phospholipids that are found in the Schwann cells. It may be possible that the body becomes immunized to specific neuronal cell membrane components. It would be fairly simple and interesting to compare the demographics of Alzheimer's and asthma or other chronic inflammatory diseases of the lung.—Michael Wider, PhD<mwider@flintink.com>

HSV-1 Is Frequently Found in the Brain—Posted 29 January 2004

See also the ARF Live Discussion: The Pathogen Hypothesis—Posted 30 July 2004

As you probably know, herpes simplex virus type 1 (HSV-1) infects 85-95 percent of the U.S. population, and a similar proportion of most of the world. The virus typically enters the body through the oral or nasal passages, and then utilizes retrograde axonal transport mechanisms to migrate to the trigeminal ganglia. The virus does not stop migrating at this point—it continues following major nerves into the brain stem (pons) using the same retrograde mechanism. Approximately 70-85 percent of people seem to halt the penetration of the virus into the brain with an immune response which in part involves the astrocytes[1]. This means that the virus actually migrates into the brains of 15-30 percent of the general population[2-8]. Pathology in the brain stem has been noted in Alzheimer's[9,10].

HSV-1 Protein VP22 Is a MAP Similar to Tau in Functionality and Perhaps in Shape
The HSV-1 microtubule organizing protein VP22 plays a major role in intracellular viral assembly post-infection. This protein is similar to tau in its functionality[11]. Consequently, VP22 may play a role in Alzheimer's pathology, as well. An amino acid sequence comparison of tau to VP22 reveals some homology which may be significant in confirming involvement of HSV-1 in AD. This homology could be especially important if labeled antibodies to tau cross-react with VP22, confounding any attempts to identify the separate influences of each within the brain.

Transition Metals Affect MAPs and Amyloid-β
It is widely known that transition metals such as zinc and aluminum are associated with increasing severity of the pathology in AD. One reason for this may be the damaging effects of these metals on microtubule-associated proteins—MAPs[12-14]. Aluminum has been found within tangles[15]. The damage to MAPs by metals may be one reason that decades-old treatments which contain aluminum still remain in use for treating herpesviruses today, since these metals could affect VP22. These treatments include the Domeboro and Burrow's solutions for herpes zoster[16], which contain aluminum acetate. Another time-proven remedy for HSV-1 is Carmex, an alum-containing lip balm. Articles on the merits of aluminum for treating herpes have been published[17,18]. Thus, contrary to popular belief, the aluminum in these products seems to be providing some medical benefit beyond simply "drying out" the lesions.

While copper and zinc are noted to inactivate herpesvirus[19,20], it is also noted that a copper/zinc chelator had a profound effect on the disappearance of plaques in a mouse model of AD[21]. Thus, there may be a link between the disruption of MAPs caused by transition metals and the appearance of tangles and plaques. This link could involve VP22, since the metals act similarly on VP22 as they do on tau.

Zinc has been noted to allow the exit of amyloid-β peptide from within cells[22]. Recently, a significant degree of structural and functional homology was shown between a fragment of HSV-1 glycoprotein B and amyloid-β peptide[23]. This may point to a role for HSV-1 in the formation of plaques and/or tangles in AD.

Free Radical Scavenging by Heavy Metals Depletes Energy Source for HSV
The negative effects of transition metals on HSV-1 may not be limited to damaging the critical viral assembly protein VP22. A final negative consequence of transition metals for HSV is that they are reducing agents. The main sources of metabolic energy for HSV-1 during latency are free radicals such as O2-, which may be processed with an alkyl hydroperoxide-type reductase encoded by the latency associated transcript (LAT). This metabolic pathway is supported by observation that HSV infection induces a time-dependent lipid peroxidation of HeLa cell plasma membranes[24], as well as other observations about the effect of the virus on local redox conditions[25-28]. Lastly, singlet oxygen has been noted to completely deactivate HSV[29,30], further supporting the case that the virus needs free radicals to thrive, since singlet oxygen does not have an extra electron to donate to the HSV enzyme and could act as a reducing agent by reverting to O2-.

Thus, the elimination of free radicals by transition metals takes away the key driver for metabolic events in HSV-1 and causes viral assembly by VP22 to come to a halt. Without free radicals, the phosphorylation of VP22 may cease and the protein can no longer act as an assembler for virions[31-33]. This may explain how metals such as aluminum, zinc, and copper deactivate herpesviruses.

Without a supply of free radicals for driving the creation of new virions, HSV-1 would no longer be able to maintain latency in the traditional sense of continuing to create new copies of virus. Further, the latency-associated transcript, which includes the enzyme that uses free radicals as a substrate, would no longer have energy to maintain itself. The failure of the latency associated transcript may be associated with apoptosis, since the LAT itself has been noted to promote neuronal survival by blocking apoptosis[34-36]. Thus, the death of an HSV-infected neuron could inadvertently occur due to the lack of free radicals caused by the presence of transition metals. If the neuron dies, then it could release many copies of partially assembled virions into the intracellular space. These unassembled particles could then form plaques, perhaps by combining with some human proteins.

Mechanism of Action of Indomethacin in AD Consistent with HSV Biology
A small, brief clinical trial demonstrated a positive effect of indomethacin, an NSAID, in halting the cognitive decline of AD[37]. This drug has also been shown to block the reactivation of latent HSV-1[38]. Other studies have reached similar conclusions [39,40]. If HSV were a causal agent of cognitive decline, then the activity of indomethacin in inhibiting the generation of free radicals by blocking prostaglandin synthesis would also serve to diminish the main metabolic source for HSV, limiting its spread through the brain.

The Immune Conundrum: Complement-Amyloid-β Complex Affected by Metal Ions Which May Be Derived from HSV Proteins
Amyloid-β binds C1q, which in turn facilitates phagocytosis by microglia[41]. The C1q binding event enhances formation of the neurotoxic, fibrillar β-pleated form of amyloid-β[41]. This point, taken in context with reference 22 stating that amyloid-β binding to copper or zinc produces an ordered, membrane-penetrating structure, may imply that C1q effects its change on amyloid-β by removing copper or zinc and allowing it to bind to C1q. This could be very problematic for the healthy functioning of the neuroimmune system, as C1q is inhibited by transition metal ions[42]. Thus, while C1q binds to β amyloid as it should, if the complex were to contain an HSV protein-transition metal complex, such as a zinc finger protein or VP22-zinc/aluminum/copper, then the entire combination could exist in a state of immunological stasis, with microglial cells unable to properly ingest the complex of proteins due to an inactivated C1q. Consequently, any plaques which form from metal-containing proteins might persist in the intracellular space for long periods, as they do in Alzheimer's disease. —Eli Kammerman (elikam@comcast.net)

A. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000 Oct;57(10):1439-1443. Abstract

B. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet. 2000 Nov 11;356(9242):1627-1631. Abstract

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2. Boggian I, Buzzacaro E, Calistri A, Calvi P, Cavaggioni A, Mucignat-Caretta C, Palu G. Asymptomatic herpes simplex type 1 virus infection of the mouse brain. J Neurovirol 2000 Aug;6(4):303-313. Abstract

3. Dobson CB, Itzhaki RF. Herpes simplex virus type 1 and Alzheimer's disease. Neurobiol Aging 1999 Jul;20(4):457-465. Abstract

4. Arbusow V, Strupp M, Wasicky R, Horn AK, Schulz P, Brandt T. Detection of herpes simplex virus type 1 in human vestibular nuclei. Neurology 2000 Sep 26;55(6):880-882. Abstract

5. Song GY, Jia W. The heterogeneity in the immune response and efficiency of viral dissemination in brain infected with herpes simplex virus type 1 through peripheral or central route. Acta Neuropathol (Berl) 1999 Jun;97(6):649-656. Abstract

6. Arbusow V, Schulz P, Strupp M, Dieterich M, von Reinhardstoettner A, Rauch E, Brandt T. Distribution of herpes simplex virus type 1 in human geniculate and vestibular ganglia: implications for vestibular neuritis. Ann Neurol 1999 Sep;46(3):416-419. Abstract

7. Baringer JR, Pisani P. Herpes simplex virus genomes in human nervous system tissue analyzed by polymerase chain reaction. Ann Neurol 1994 Dec;36(6):823-829. Abstract

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10. Ishino H, Otsuki S. Frequency of Alzheimer's neurofibrillary tangles in the basal ganglia and brain-stem in Alzheimer's disease, senile dementia and the aged. Folia Psychiatr Neurol Jpn 1975;29(3):279-287. Abstract

11. Elliott G, O'Hare P. Herpes simplex virus type 1 tegument protein VP22 induces the stabilization and hyperacetylation of microtubules. J Virol 1998 Aug;72(8):6448-6455. Abstract

12. Muma NA, Singer SM. Aluminum-induced neuropathology: transient changes in microtubule-associated proteins. Neurotoxicol Teratol 1996 Nov;18(6):679-690. Abstract

13. Singer SM, Chambers CB, Newfry GA, Norlund MA, Muma NA. Tau in aluminum-induced neurofibrillary tangles. Neurotoxicology 1997;18(1):63-76. Abstract

14. Savory J, Huang Y, Wills MR, Herman MM. Reversal by desferrioxamine of tau protein aggregates following two days of treatment in aluminum-induced neurofibrillary degeneration in rabbit: implications for clinical trials in Alzheimer's disease. Neurotoxicology 1998 Apr;19(2):209-214. Abstract

15. Perl DP, Brody AR. Alzheimer's disease: X-ray spectrometric evidence of aluminum accumulation in neurofibrillary tangle-bearing neurons. Science 1980 Apr 18;208(4441):297-299. Abstract

16. Glaxo-Wellcome VZV Infection Website.

17. Karnaky KJ. Letter: Micronized aluminum powder for treatment of herpes genitalis. Am J Obstet Gynecol 1974 Jun 15;119(4):574. Abstract

18. Hurt WC. Treatment of herpes labialis with aluminum potassium sulfate. Tex Dent J 1971 Jan;89(1):21-22. Abstract

19. Arens M, Travis S. Zinc salts inactivate clinical isolates of herpes simplex virus in vitro. J Clin Microbiol 2000 May;38(5):1758-1762. Abstract

20. Sagripanti JL, Routson LB, Bonifacino AC, Lytle CD. Mechanism of copper-mediated inactivation of herpes simplex virus. Antimicrob Agents Chemother 1997 Apr;41(4):812-817. Abstract

21. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y, Huang X, Goldstein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL, Bush AI. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 2001 Jun;30(3):665-676. Abstract

22. Curtain CC, Ali F, Volitakis I, Cherny RA, Norton RS, Beyreuther K, Barrow CJ, Masters CL, Bush AI, Barnham KJ. Alzheimer's disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J Biol Chem 2001 Jun 8; 276(23):20466-20473. Abstract

23. Cribbs DH, Azizeh BY, Cotman CW, LaFerla FM. Fibril formation and neurotoxicity by a herpes simplex virus glycoprotein B fragment with homology to the Alzheimer's A beta peptide. Biochemistry 2000 May 23;39(20):5988-5994. Abstract

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Physiological Processes Gone Awry

Ependymal Stem Cell Niche Disruption Hypothesis—Posted 23 March 2010
By Milan Radojicic

Ependymal cells line the inner cerebrospinal fluid pathways of the brain and spinal cord. They are critical for cerebrospinal fluid homeostasis, cellular signaling, and wound repair in the brain and spinal cord (1). Cells of the ependymal region are vestiges of neuroepithelial cells (a subtype of stem cells) that give rise to neurons and glia during mammalian development (2) and are known to orchestrate the regenerative response in tailed amphibians (3). Ependymal region cells have been shown to proliferate and migrate following central nervous system injury (2,4-6). Indeed, the kinetics of ependymal region cell proliferation and differentiation has been correlated with the recovery of lower limb motor function in rats following contusion injuries (6).

Of note, neural stem cells have been isolated from the adult central nervous system (7-10), including regions near the subventricular zone and the central canal. Neurogenesis has been reported from the adult subventricular zone (11). Additionally, gliogenesis has been reported from the brain and spinal cord, as well, including the generation of new ependymal cells (4), reactive astrocytes (6,7,12), oligodendrocyte precursors (13), and microglia (14). Glia are the supportive cells of the central nervous system and are critical for maintaining the structural and functional integrity of the brain and spinal cord after injury. Therefore, disruption of the ependyma could have profound effects on brain and spinal cord function which may have implications for neurodegenerative disorders, such as Alzheimer disease. Sources of this disruption could include local ischemia, changes in cerebrospinal fluid dynamics, and the composition of the cerebrospinal fluid.

Normally, cerebrospinal fluid circulates in the subarachnoid space, traverses the brain and spinal cord several times a day, and exhibits a craniocaudal flow pattern influenced by the cardiac cycle. The cerebrospinal fluid is produced by ependymal cells and is absorbed in the dural venous sinuses and along lymphatic channels near the nerve roots. Some cerebrospinal fluid, driven by the heart’s systolic pulsations, is thought to enter the substance of the brain and spinal cord via the Virchow-Robin perivascular spaces and flow toward the ventricles and central canal, essentially bathing the brain and spinal cord’s extracellular space. This process is thought to clear the brain and spinal cord of harmful substances generated during metabolism, thereby “flushing” away the byproducts. Therefore, disturbances in this process through ependymal dysfunction could have profound effects on the brain and spinal cord, which may have implications for neurodegenerative disease, such as Alzheimer disease.

Ependymal cells are ciliated cells that line the ventricular cavity and are critical for maintaining cerebrospinal fluid homeostasis, cerebrospinal fluid hydrodynamics, and the local sub-ependymal stem cell niche. Cilia are specialized projections of ependymal cells that promote the flow of cerebrospinal fluid along the brain and spinal cord (15). Ependymal ciliary loss is known to predispose to hydrocephalus (15) and is a feature of the disease (16). Therefore, loss of cilia could have profound effects on cerebrospinal fluid propulsion, leading to alterations in cerebrospinal fluid homeostasis and cerebrospinal fluid dynamics. Changes in the clearance of certain brain metabolites have been hypothesized in the pathogenesis of Alzheimer disease (17). Ependymal ciliary loss may be a mechanism in this process. This loss of ependymal cell cilia may result in a local stasis and accumulation of cerebrospinal fluid adjacent to the ependyma, leading to an accumulation of toxic levels of electrolytes and metabolites and proteins in the ependymal and peri-ependymal areas, and subsequently the substance of the brain itself. This impaired clearance of proteins in the brain tissue could be thought of by analogy as a form of "protein-neuria.” Normal adults do demonstrate ciliary loss in the ventricles, which could be thought of as an early form of senescence, but other factors are certainly at work in the development of complex neurodegenerative diseases such as Alzheimer’s dementia.

The ependyma are known to receive a vascular supply from very small sub-ependymal arteries (18), making them very susceptible to microvascular disease, such as that which occurs with diabetes and cardiovascular disease. Diabetes and cardiovascular disease are known to increase the risk of Alzheimer disease. Moreover, changes in periventricular blood flow have been documented as an early finding in various causes of dementia (19). Therefore, beyond mere ciliary loss, disruption of the ependymal epithelium lining itself through local ischemia, buildup of toxic metabolites, and pressure gradients could lead to profound changes in brain function.

Normally, the ependyma consists of a pseudo-stratified monolayer of cells that plays an important role in cerebrospinal fluid homeostasis by regulating fluid and electrolyte balance between the cerebrospinal fluid and the substance of the brain and spinal cord (4). Disruption and denudation of the ependymal layer could therefore result in the loss of a protective epithelium. This incompetence of the ventricular linings would lead to an exposure of the adjacent grey and white matter to pressure gradients and an eventual dissection of non-circulating cerebrospinal fluid from within the ventricles and canal. Ependyma disruption has been documented following exogenous toxin administration (20), so should result equally with accumulation of internal toxins. Furthermore, fluid from non-circulating cerebrospinal fluid collections, such as subdural hematomas, is known to differ from normal cerebrospinal fluid, usually having a higher protein content, which may give rise to oncotic pressures (21). Prolonged exposure of peri-ependymal tissues to this microenvironment may lead to structural degeneration as well as functional deficits, such as conduction failures. Eventually, local disruptions of the blood-brain barrier may contribute to the edema, but also may represent a source of additional inflammatory molecules and plasma proteins that may adversely influence the microenvironment of nearby cells, including cells with stem/progenitor characteristics, thereby influencing their viability and patterns of differentiation. Indeed, the presence of serum in ependymal cell cultures leads to differentiation into lineages associated with scarring (22). Beyond Alzheimer disease, this latter process may have profound implications for other neurodegenerative diseases such as multiple sclerosis and amyotrophic lateral sclerosis.

Finally, it stands to reason that disruption of the ependymal stromal epithelium, along with peri-ependymal stem/progenitor cells, may represent a heretofore unrecognized pathogenic mechanism in neurodegenerative disorders such as Alzheimer disease. Loss of sub-ependymal stem cells would hinder neurogenesis and gliogenesis (i.e., self-repair) in the ependymal region (including the replacement of damaged ependymal cells). Moreover, because these cells are known to migrate in disease and injury, loss of sub-ependymal stem cells would eventually lead to loss of self-repair in the entire brain and spinal cord. Indeed, the progressive disruption of this ependymal region, through ischemic, mechanical, and cytotoxic means, could represent a disease mechanism that tips the balance between injury and repair in the brain toward further cyto-architectural destruction of lesions over time, with profound effects on cognitive abilities. As an example, there is a rostral migratory stream of neuronal precursors from the subventricular zone towards the olfactory bulb (23). Disruptions in neurogenesis would therefore result in a loss of the sense of smell. Of note, anosmia is a known early symptom of several neurodegenerative disorders, including Alzheimer disease.

Therefore, bypassing ependymal dysfunction through cerebrospinal dialysis procedures may be a temporizing measure until a true repair of the ependymal region is possible.

Taken from “On the role of ependymal disruption in neurodegeneration.” Copyright 2004-2010 Milan Radojicic MD. All rights reserved. Used with permission by author.

See Neurosyntec LLC for additional information.

References
1. Radojicic M, Nistor G, Keirstead HS. Ascending central canal dilation and progressive ependymal disruption in a contusion model of rodent chronic spinal cord injury. BMC Neurol 2007;7:30. Abstract

2. Vaquero J, Ramiro MJ, Oya S, Cabezudo JM. Ependymal reaction after experimental spinal cord injury. Acta Neurochir (Wien) 1981;55(3-4):295-302. Abstract

3. Chernoff EAG, Stocum DL, Nye HLD, Cameron JA. Urodele spinal cord regeneration and related processes. Dev. Dyn 2003 Feb;226(2):295-307. Abstract

4. Bruni JE, Anderson WA. Ependyma of the rat fourth ventricle and central canal: response to injury. Acta Anat (Basel) 1987;128(4):265-273. Abstract

5. Matthews MA, St Onge MF, Faciane CL. An electron microscopic analysis of abnormal ependymal cell proliferation and envelopment of sprouting axons following spinal cord transection in the rat. Acta Neuropathol 1979 Jan;45(1):27-36. Abstract

6. Takahashi M, Arai Y, Kurosawa H, Sueyoshi N, Shirai S. Ependymal cell reactions in spinal cord segments after compression injury in adult rat. J. Neuropathol. Exp. Neurol 2003 Feb;62(2):185-194. Abstract

7. Johansson CB, Momma S, Clarke DL, Risling M, Lendahl U, Frisén J. Identification of a neural stem cell in the adult mammalian central nervous system. Cell 1999 Jan;96(1):25-34. Abstract

8. Weiss S, Dunne C, Hewson J, Wohl C, Wheatley M, Peterson AC, Reynolds BA. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J. Neurosci 1996 Dec;16(23):7599-7609. Abstract

9. Yamamoto S, Yamamoto N, Kitamura T, Nakamura K, Nakafuku M. Proliferation of parenchymal neural progenitors in response to injury in the adult rat spinal cord. Exp. Neurol 2001 Nov;172(1):115-127. Abstract

10. Martens DJ, Seaberg RM, van der Kooy D. In vivo infusions of exogenous growth factors into the fourth ventricle of the adult mouse brain increase the proliferation of neural progenitors around the fourth ventricle and the central canal of the spinal cord. Eur. J. Neurosci 2002 Sep;16(6):1045-1057. Abstract

11. Doetsch F. A niche for adult neural stem cells. Curr. Opin. Genet. Dev 2003 Oct;13(5):543-550. Abstract

12. Mothe AJ, Tator CH. Proliferation, migration, and differentiation of endogenous ependymal region stem/progenitor cells following minimal spinal cord injury in the adult rat. Neuroscience 2005;131(1):177-187. Abstract

13. Miller RH, Ono K. Morphological analysis of the early stages of oligodendrocyte development in the vertebrate central nervous system. Microsc. Res. Tech 1998 Jun;41(5):441-453. Abstract

14. Carbonell WS, Murase S, Horwitz AF, Mandell JW. Infiltrative microgliosis: activation and long-distance migration of subependymal microglia following periventricular insults. J Neuroinflammation 2005 Jan;2(1):5. Abstract

15. Afzelius BA. Cilia-related diseases. J. Pathol 2004 Nov;204(4):470-477. Abstract

16. Kiefer M, Eymann R, von Tiling S, Müller A, Steudel WI, Booz KH. The ependyma in chronic hydrocephalus. Childs Nerv Syst 1998 Jun;14(6):263-270. Abstract

17. Silverberg GD, Mayo M, Saul T, Fellmann J, Carvalho J, McGuire D. Continuous CSF drainage in AD: results of a double-blind, randomized, placebo-controlled study. Neurology 2008 Jul;71(3):202-209. Abstract

18. Marinkovic S, Gibo H, Filipovic B, Dulejic V, Piscevic I. Microanatomy of the subependymal arteries of the lateral ventricle. Surg Neurol 2005 May;63(5):451-458; discussion 458. Abstract

19. Silverberg GD. Normal pressure hydrocephalus (NPH): ischaemia, CSF stagnation or both. Brain 2004 May;127(Pt 5):947-948. Abstract

20. Avila-Costa MR, Colín-Barenque L, Zepeda-Rodríguez A, Antuna SB, Saldivar O L, Espejel-Maya G, Mussali-Galante P, del Carmen Avila-Casado M, Reyes-Olivera A, Anaya-Martinez V, Fortoul TI. Ependymal epithelium disruption after vanadium pentoxide inhalation: A mice experimental model. Neuroscience Letters 2005 Jun;381(1-2):21-25. Abstract

21. Weir B. Oncotic pressure of subdural fluids. J. Neurosurg 1980 Oct;53(4):512-515. Abstract

22. Brisson C, Lelong-Rebel I, Mottolèse C, Jouvet A, Fèvre-Montange M, Saint Pierre G, Rebel G, Belin MF. Establishment of human tumoral ependymal cell lines and coculture with tubular-like human endothelial cells. Int. J. Oncol 2002 Oct;21(4):775-785. Abstract

23. Whitman MC, Greer CA. Adult neurogenesis and the olfactory system. Prog. Neurobiol 2009 Oct;89(2):162-175. Abstract

Could Hyponatremia Be the Root Cause of Alzheimer's?—Posted 26 October 2009
By Gregory Marlow

Hyponatremia (low blood sodium) is known to cause osmotic swelling of the brain. If this swelling is severe enough it could cause damage to the brain. Other tissues that receive physical damage (like the skin to a burn or a harsh whip) respond with inflammation. If the tissue of the brain responds in a similar fashion, inflammation that has been associated with Alzheimer’s amyloid plaque formation could be the result (1). The incidence of hyponatremia in the healthy elderly has been estimated at 7 percent, and among elderly in nursing homes it has been reported as high as 15-18 percent (2). One way hyponatremia results in the elderly is from a decreased ability of the kidneys to reabsorb sodium (3). The high salt diet of Asians and Indians may decrease the risk of hyponatremia and thus explain their lower incidence of Alzheimer’s. The low sodium recommendation by Western medicine to reduce hypertension may increase the risk of hyponatremia. Lack of sleep is a possible risk factor for Alzheimer’s (4). Salt levels influence the quality and quantity of sleep; lower levels worsen sleep (5). Low testosterone levels have been linked to Alzheimer's (6). Low testosterone is also responsible for low sodium reabsorption by the kidneys (7). Some other mental illnesses have also been linked to Alzheimer's (8,9). Hospital admissions to mental wards are 10 times (10.5 percent) (10) more likely to be hyponatremic than all other admissions (1 percent) (11). A high salt diet may not be an appropriate treatment for Alzheimer disease because of its possible negative effects. But if it turns out that low salt is the culprit, it will go a long way to finding a cure.

1. Inflammation May Trigger Alzheimer’s Disease
2. Hyponatremia and Hypernatremia in the Elderly
3. Fluid Balance Disorders in the Elderly [.pdf]
4. Lack of Sleep May Increase the Risk of Alzheimer's Disease
5. Salt and Sleep
6. Low Free Testosterone Levels Linked to Alzheimer’s Disease in Older Men
7. Sodium-induced Rise in Blood Pressure Is Suppressed by Androgen Receptor Blockage [.pdf]
8. Schizophrenia, Alzheimer’s Disease and Anti-inflammatory Agents [.pdf]
9. Depression and Alzheimer’s Linked
10. An Epidemiological Study on Hyponatremia in Psychiatric Patients in Mental Hospitals in Nara Prefecture
11. Electrolyte Balance

Involvement of RELB in AD—Posted 25 September 2009
By John Neu

This hypothesis is based on the following:

• AD is an immune disease.
• APOE is involved but not the causative gene; rather, mutations in a nearby gene (RELB) are the main risk factors.
• RELB is located 92 kbp downstream from APOE.
• RELB is a member of the NFκB transcription factors (REL proteins) central to all immunological functions and are the primary transcription factors involved in aging.
• Nearly all genes involved in AD have functional NFκB sites in their promoters.
• RELB has not been looked at in any detail in AD patients and only a small number of SNPs across the entire gene are found on any of the available SNP chips, so present screens may not pick up any associations.
• RELB controls transcription primarily by inhibition (also called IREL), which can be by direct binding and interaction with transcription machinery or epigenetic through DNA methylation.
• Some of the genes shown to be regulated by RELB are also associated with AD (e.g., DAPK1, IL1β, TNFα, COX-2, and MnSOD). And some that regulate RELB (e.g., RELA, VDR) have also shown some association.

Ontogenesis, Breast Milk Childhood Intelligence and AD—Posted 18 May 2001

I would appeciate feedback on the possibility that early brain development or aberrant development/synaptogenesis/myelination may predispose to the development of AD in the adult. This notion came to mind after perusing the literature and contemplating the important role several AD-linked genes play in neuron development and synaptic plasticity (ie APP, synuclein, presenilin). On a separate unrelated query investigating the benefits of breast feeding, I came across several articles supporting a link between breast feeding and childhood intelligence. A curious association given that higher educational attainment has been reported as being protective in AD. Recently, Whalley et al demonstrated a link between lower childhood intelligence and late-onset dementia. Braak and Rosenberg have pointed out in several papers that the chronological/spatial development of NFT pathology in AD reflects the reverse pattern of myelination in the developing brain (retrogenesis). Could there be a possible link between breast milk, brain development, childhood intelligence and AD? Breast milk is particularly rich in long-chain polyunsaturated fatty acids, which are essential for brain growth and myelination. Could poor early CNS myelination related to neonatal diet be that link? Has the possibility that breast-fed children might be protected from the development of AD been looked at more closely, and is anyone aware of a database in which a study of this type could be performed? Perhaps neonatal information such as OFC, formula/breast milk nutrition and early childhood intelligence levels would be available in the Nun population records? —Mark Fishel (mafishel@u.washington.edu)

Comment by June Kinoshita (junekino@alzforum.org) —Posted 18 May 2001

I've also wondered about the effects of FAD mutations on early brain development. In mice, these mutations result in apparently "normal" brains, but I wonder if anyone has done the really painstaking analysis of cell and synapse counts, microstructural anomalies, etc.?

Re: breastfeeding and childhood intelligence, I don't know if these studies have controlled for socioeconomic and education factors, as well as for changes in cultural attitudes towards breastfeeding over the past century. In our society, I suspect that rates of breastfeeding (in recent times) have been signficantly higher among more educated mothers, who are better informed about the benefits of breastfeeding, and are also more likely to have the economic means to take an extended maternal leave and therefore be able to breastfeed (returning to a job usually means the end of breastfeeding). In the middle of the 20th century, it may have been that wealthier women were more likely to bottlefeed, although one presumes that poorer women were more likely to hold jobs and would therefore have welcomed bottlefeeding. This kind of stuff cries out for hard data. There must be some around...

Secretory Vesicle Defect and AD? —Posted 6 April 2001

I am a student in Korea. I am happy to meet this site, and hope others will give me advice on future research directions for AD. I think impaired scretetory vesicle release of neurotransmitter induces neurodegeneration and AD. I am interested in the idea of proteins that are involved in secretory vesicle release of neurotransmitter interacting with other proteins that play a role in AD (or in APP processing). If anyone has insights to offer on my idea, please give me your opinion. Thank you!! —Mi Kyung Hwang anise@hanwha.co.kr

Glycation Theory of Aging—Submitted 21 July 1997

"Another prominent theory relating fuel utilization to damage and aging holds that toxic effects of glucose may mediate aging processes. Glucose and other reducing sugars undergo nonenzymatic glycation reactions with proteins and nucleic acids to generate glycoadducts termed advanced glycosylation end-products (AGEs). It has been proposed that AGEs cause aging by cross-linking or otherwise modifying biologic molecules involved in critical physiologic processes. The glycation theory of aging is especially provocative because recent studies demonstrating prevention of AGE formation by aminoguanidine suggest potential interventions to retard aging processes."

From Stein Internal Medicine 4th Ed. [1994] on STAT! Ref CD ROM Summer 1997

A search of Harrison's for "glycation"r eveals the following documents in relation to glycation, but a very significant point that is easily overlooked is the role of fructose; key player in the pathophysiology of glycation may well be fructose; note especially the sentence from Harrison in the text below, reproduced here :- " The rate of glycation with fructose is seven or eight times faster than with glucose"; what damage could be expected in the long term with a high fructose diet in susceptible individuals; whilst the paragraghs from Harrison relate to diabetes, are the

Extracts from Harrison follow:

What causes the complications of diabetes?

The cause of diabetic complications is not known and may be multifactorial. Major emphasis has been placed on the polyol pathway, wherein glucose is reduced to sorbitol by the enzyme aldol reductase. Sorbitol, which appears to function as a tissue toxin, has been implicated in the pathogenesis of retinopathy, neuropathy, cataracts, nephropathy, and aortic disease. The mechanism is perhaps best worked out in experimental diabetic neuropathy, where sorbitol accumulation is associated with a decrease in myoinositol content, abnormal phosphoinositide metabolism, and a decrease in Na+, K+-ATPase activity. In experimental models, primacy of the polyol pathway in initiating neuropathy was proven by showing that inhibition of aldol reductase prevented the fall in tissue myoinositol content and the decrease in ATPase activity. Myoinositol deficiency was not found in sural nerve biopsies from humans with diabetic neuropathy, in contrast to animals. Aldol reductase inhibition also has been shown to prevent experimental cataracts and retinopathy. It thus seems possible that neuropathy and retinopathy are primarily due to activation of the polyol pathway. It also may play a role in diabetic nephropathy.

A second mechanism of potential pathogenetic importance is glycation of proteins. (Current terminology uses glycation for nonenzymatic addition of hexoses to proteins and glycosylation for enzymatic addition.) The effect of such glycation on hemoglobin has been mentioned, but multiple proteins in the body are altered in the same way, often with disturbed function. Examples include plasma albumin, lens protein, fibrin, collagen, lipoproteins, and the glycoprotein recognition system of hepatic endothelial cells. Particularly intriguing is the effect of glycation on lipoproteins. Glycated LDL is not recognized by the normal LDL receptor, and its plasma half-life is increased. Conversely, glycated HDL turns over more rapidly than native HDL. It also has been reported that glycated collagen traps LDL at rates two to three times greater than normal collagen.

Glycated collagen is less soluble and more resistant to degradation by collagenase than native collagen. However, it is not clear that this is related either to the basement membrane thickening or to the tight, waxy skin syndrome with limited joint mobility (scleroderma-like) seen in some patients with insulin-dependent diabetes (see "Miscellaneous Abnormalities," below). Although it is attractive to presume that nonenzymatic glycation of protein plays a role in some degenerative complications, the evidence is less direct than with the polyol pathway. Linkage between the polyol pathway and the glycation sequence occurs as a result of the glycation of collagen and other proteins by fructose generated from sorbitol. The rate of glycation with fructose is seven or eight times faster than with glucose.

Glycated proteins also form advanced glycation end products (AGE) through a series of biochemical reactions that are poorly understood. Receptors for AGE are present on macrophages and endothelial cells. Binding of AGE to the receptors may induce the release of cytokines, endothelin-1, and tissue factor. The latter plays a preeminent role in the initiation of coagulation. Experimentally, AGE formation may be impaired or prevented by aminoguanidine, an agent currently in clinical trials in humans. In animals, it has a beneficial effect in prevention of retinopathy, nephropathy, and neuropathy (commonly called microvascular complications), but it is projected to have its major effect in atherosclerotic complications (commonly called macrovascular complications).

Increased blood flow has been postulated to play an initiating role in diabetic complications, possibly by increasing filtration of macromolecules that function as tissue toxins. There is supportive evidence for a role of hyperperfusion in diabetic nephropathy, but the hemodynamic hypothesis does not appear as attractive as the first two.

Monitoring control of diabetes

( HbA1c = glycated Hb Ed.)

For those patients who measure blood glucose frequently for adjustment of insulin dosage, an estimate of mean ambient glucose concentrations is readily available. For other patients, and as a check on accuracy of the self measurements, most diabetologists measure hemoglobin A1c to assess long-term control. Hemoglobin A1c, a fast-moving minor hemoglobin component, is present in normal persons but increases in the presence of hyperglycemia. Its enhanced electrophoretic mobility is due to nonenzymatic glycation of the amino acids valine and lysine.

Glucose in the aldehyde (linear) configuration condenses with a free amino group to form a Schiff base (aldimine or pre-A1c). The Schiff base undergoes a rearrangement to form hemoglobin A1c, a ketoamine. Aldimine formation is reversible so that pre-A1c is labile, while ketoamine formation is irreversible and thus stable. Pre-A1c levels change rapidly with alterations in glucose concentrations and do not reflect long-term control, although they are measured in chromatographic methods for determining hemoglobin A1c. Pre-A1c must thus be removed to assess true Hb A1c values accurately. Many laboratories employ high-performance liquid chromatography to make the measurement. A colorimetric method utilizing thiobarbituric acid also does not measure the labile pre-A1c fraction. When properly assayed, the percent of glycated hemoglobin gives an estimate of diabetic control for the preceding 3-month period. Normal values must be obtained for each lab; on average, nondiabetic subjects have Hb A1c values of less than 6 percent, while levels in poorly controlled patients may reach 10 to 12 percent. Measurement of glycated hemoglobin gives an objective assessment of metabolic control. Discrepancies between reported plasma glucose values and hemoglobin A1c concentrations suggest either that measurement or reporting of the former is not accurate. Measurement of glycated albumin, because of its short half-life, can be used to monitor diabetic control over a 1- to 2-week period but clinically is rarely used.

Circulatory abnormalities

Atherosclerosis occurs more extensively and earlier than in the general population. The cause for this accelerated atherosclerosis is not known, although, as discussed below, nonenzymatic glycation of lipoproteins may be important. The atherosclerotic lesion appears to be initiated by oxidized low-density lipoproteins (LDL) (not native LDL) in a complicated cascade that operates through the acetyl-LDL or scavenger receptor. Both high-density lipoproteins (HDL) and antioxidants have the capacity to impair LDL oxidation, thereby exerting an antiatherogenic action. In experimental animals, diabetes accelerates the oxidative process. Although lipoproteins are often in the normal range, HDL levels tend to be low, while LDL levels are high normal or high. A high LDL/HDL ratio favors atherogenesis, and with lower HDL levels reverse cholesterol transport (from established lesions) would be impaired. Lipoprotein (a) levels are elevated in IDDM but not NIDDM.

Other factors of potential importance are increased platelet adhesiveness, possibly due to enhanced thromboxane A2 synthesis, and decreased prostacyclin synthesis. Hyperglycemia has been reported to increase secretion of endothelin-1 in vitro, and production of nitric oxide is diminished in aortas of diabetic rats and the coronary microvasculature of humans. These findings have not been confirmed in human diabetes. Endothelin is a powerful vasoconstrictor and is mitogenic for vascular smooth muscle, while nitric oxide is a vasodilator, is antimitogenic in vascular smooth muscle, and inhibits platelet aggregation.

Advanced glycation end products may be important, as discussed below

Atherosclerotic lesions produce symptoms in a variety of sites. Peripheral deposits may cause intermittent claudication, gangrene, and, in men, organic impotence on a vascular basis. Surgical repair of large-vessel lesions may be unsuccessful because of the simultaneous presence of widespread disease of the small vessels. Coronary artery disease and stroke are common. Silent myocardial infarction is thought to occur with increased frequency in diabetes and should be suspected whenever symptoms of left ventricular failure appear suddenly. Diabetes also may be associated with the clinical picture of cardiomyopathy, in which heart failure occurs in the face of angiographically normal coronary arteries and the absence of other identifiable causes of heart disease. As in nondiabetic subjects, smoking is a major risk factor for both coronary and peripheral vascular disease and should be avoided. Hypertension is also a significant risk factor in many diabetic patients.

Can diabetic complications be prevented by meticulous control of diabetes?

As mentioned earlier, the strongest evidence that the answer is yes comes from the Diabetes Control and Complications Trial (DCCT). Additional clinical evidence supports the view that metabolic environment per se influences or causes complications independent of genetic factors. For example, kidneys from donors who have neither diabetes nor a family history of diabetes develop characteristic lesions of diabetic nephropathy within 3 to 5 years after transplantation into a diabetic recipient. Diabetic nephropathy did not develop when a kidney was transplanted into a diabetic subject whose disease had been reversed by pancreatic transplantation prior to renal transplantation. It also has been reported that kidneys manifesting diabetic nephropathy demonstrated reversal of the lesion when transplanted into normal recipients. All these findings suggest that hyperglycemia or some other aspect of the abnormal metabolism of diabetes causes or influences the development of complications. On the other hand, additional factors, probably genetic, must normally play a role. This follows from the fact that diabetic subjects with decades of poor control may escape the ravages of the late complications and from the fact that typical diabetic complications may be found in patients at the time of diagnosis of diabetes or even in the absence of hyperglycemia.

Meticulous control with insulin infusion pumps has been reported to decrease microalbuminuria, improve motor nerve conduction velocity, lower plasma lipoproteins, and decrease capillary leakage of fluorescein in the retina. Width of the capillary basement membrane in skeletal muscle also has been decreased. The changes are small in general, however, and of questionable biologic significance. Thus firm evidence does not exist to show that late complications can be reversed by long-term near-normalization of the plasma glucose level. Progression of retinopathy has been reported despite successful reversal of diabetes by pancreatic transplantation. The progression of diabetic complications after return of the plasma glucose level to normal or near normal has been termed hyperglycemic memory.

Some investigators suggest that the mechanism is formation of advanced glycation end products during hyperglycemia which, being irreversible, continue their effects long term

As discussed earlier, the question of intensive therapy for all patients with diabetes remains open at the time of this writing pending evidence that the results achieved in DCCT can be matched in the general population. Care of persons with diabetes is often delivered by nonspecialists who do not have available teams of support personnel, as was the case in the DCCT. There seems little question, however, that the thrust of treatment will be toward tighter control.

From "Harrison's Principles of Internal Medicine, 13/e Copyright 1994 McGraw-Hill, Inc. I would like to acknowledge the use of information from both Harrison & STAT! Ref on CD ROM. Further information on availability of these CDs are available from:- http://www.tetondata.com

Case Studies

Recovery of Function in AD Patient Following a Stroke—Posted 25 February 2004

My mother has Alzheimer's. She lived in her own home, eventually with an aide. Then she was in assisted living for two years and has been in nursing care for the past two years. She has been in a wheelchair for approximately two years and very rarely speaks appropriately—if at all.

Last week she suffered a stroke or seizure (the facility is not sure, as no MRI has been performed). She was unconscious for two days and then woke up. She is now speaking appropriately with some gibberish mixed in the middle. She will respond to questions as well as to both verbal and visual stimulation. My three-year-old son ran into the room and she said, "Oh, look at him." She hasn't even noticed him for at least one and a half years.

I said, "Okay, Mom, see you on the weekend."

She responded, "Okay, babe, see you on the weekend."

In speaking with my sister and comparing notes, we feel that she has gone back one and a half to two years in the severity of the disease. With Alzheimer's disease cases increasing and research not keeping up, I just thought that this information may be of value.

Comment from Bill Brooks:—Posted 2 March 2004

Comment from James Cooper:—Posted 8 March 2004

I've had two patients with Alzheimer's in the past year who have had dramatic improvements following serious medical events. One patient had a severe allergic reaction to a drug (sulfa allergy); the other also had what appeared to be a stroke. The families who reported the improvements are reliable historians and gave objective examples of cognitive gain.

Perhaps there are stress related cytokines that modify any inflammatory mechanisms associated with Alzheimer's. This, of course, would depend on establishing that such mechanisms are responsible for some of the symptoms.—James Cooper, MD

Comment from Jacob Raber:—Posted 17 March 2004

Hip Surgery and AD?—Posted 28 June 2005

Our mother has had dementia/Alzheimer's for about 4-5 years and has been in an Alzheimer home for about two years. Something very interesting has happened recently. Right before this incident happened, I would go to see her and she would look at me strangely, like "I know her," but she didn't know who I was. Well, then about 3 weeks ago, she fell twice and broke her hip. They took her by ambulance to a hospital and put a pin into her hip. While at the hospital, we noticed something strange. She was more coherent, knew each of us (my sister and brother), made sense in her conversations with us, etc. My brother thinks that maybe because her fear in the past 3 weeks, that maybe it has stirred all of her senses, i.e., making her more "alive and thinking" than she used to be. My brother and I went to see her about a week ago and she looked at us and said, "Oh, my firstborn and baby," which is true. We are the firstborn and the baby. They also had to send her by ambulance again to a rehab hospital. So she's been in a hospital over the past 3-4 weeks, and is two ambulance rides away from anyone she knows at all.

Just wondering if you have ever heard of something like this happening? It's nice to have her back needless to say, but it is strange. First, she had gotten to a point of not recognizing us and now she's talking and understanding everything that we say to her.

Also, at the hospital she got quite snippy with one of the nurses telling her to "shut up." This is coming from a "God-fearing woman." I was amazed.—Joan

The Irruption into Profound Dementia of a Window of Sudden Lucidity—Posted 8 June 2009

Hypothesized Treatments

Alzheimer Disease Treatment—14 June 2010

Galantamine is used as a competitive inhibitor of AChE, but I doubt that a compound such as galantamine could enter the active center of AChE. The molecular models show there is no similarity between galantamine and acetylcholine, and from my viewpoint, it is almost impossible that galantamine enters the active center of the enzyme. However, propylcholine is very similar to acetyl and butyrylcholine, and can enter the active center and act as a competitive inhibitor. This would be better for the organism, because a product such as propylcholine should be metabolized by the enzymatic system better than galantamine and produce fewer collateral effects.

What do you think about the use of phosphatidyl inositol as a treatment for AD? This metabolite is needed for the vesicles’ fusion in the synapses and the liberation of neurotransmitters, but it is possible that the second messengers, DAG, which activates PKC and α-secretase, and InsP3, which liberates Ca from the endoplasmic reticulum, could produce neurotoxicity because of the effect that Ca has over the excitatory glutamate. This is my doubt, because in spite of the fact that InsP3 produces Ca liberation, there also are activated a lot of calmodulin-type proteins that should sequester the Ca excess until a Ca equilibrium is obtained at the neurons. I’ll be very glad for your opinion about such topics.—C. Roberto Iglesias Lores

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