Summary

Suzanne de la Monte led this live discussion on 25 March 2005. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:

Live Discussion led by Suzanne de la Monte on 25 March 2005.

Participants: Shaharyar Khan, Gencia Corporation; Suzanne de la Monte, Brown Medical School ; Elana Sinsabaugh, caregiver; Mark Reger, University of Washington, VA Puget Sound Health Care System; Marcos Marques, GRI Univ Cincinnati; Nancy Emerson Lombardo, Boston University School of Medicine, Neurology and VAMC Bedford, Massachusetts; Ellen Smith, caregiver; Cyrus Raji, University of Pittsburgh; Patricia C. Heyn, University of Colorado Health Sciences Center, Division of Geriatrics; Craig Atwood, University of Wisconsin, Madison, School of Medicine; G. Stennis Watson, University of Washington, Dept. of Psychiatry; Ruthie, caregiver.

Note: The transcript has been edited for clarity and accuracy. _______________________________________________________________________

June Kinoshita
I'm June Kinoshita of the Alzforum. Suzanne, perhaps we can start by having you quickly state your main concepts in the JAD papers.

Suzanne de la Monte
Our main concepts are that Alzheimer disease (AD) may represent a neuroendocrine disease in which substantial abnormalities arise due to impairments in insulin and insulin-like growth factor (IGF) signaling. Insulin and IGF are critical for neuronal survival, and what we have found is that the levels of the polypeptide genes and their receptors are substantially reduced, preventing neurons from responding to the trophic influences. We believe these effects may be critical to neuronal function and neurodegeneration.

Nancy Emerson
Excellent reviews of the literature and the extant theories relating diabetes, insulin resistance, and AD. I am still absorbing the details of the two articles. My primary interest now is in designing a nutritional intervention for early-stage patients...with Tufts. I noted that you suggest treatment with insulin might be helpful. What are your thoughts about dietary interventions designed to increase insulin sensitivity or reduce insulin resistance?

Suzanne de la Monte
One of the interesting findings was that insulin is made in the brain. Actually, we have known this for some time, and it fits with our knowledge that all other pancreatic polypeptides are made in the central nervous system (CNS). I also believe that diet may influence this story. For example, vanadate inhibits tyrosine phosphatases, so vanadium, which is present in shellfish and lobster, may be a great supplement.

June Kinoshita
What is different about CNS insulin signaling pathways vs. peripheral pathways?

Suzanne de la Monte
CNS and peripheral insulin signaling work the same way, but we think the peripheral and CNS pathways are separated—that's good. It may explain why diabetics with acute and chronic metabolic impairments are cognitively okay for the most part.

Nancy Emerson
So how do we encourage increased insulin production in the brain? And are levels of endogenous insulin as difficult to influence as brain cholesterol, as opposed to peripheral cholesterol. This is immensely complex, biochemically, as you showed in your papers.

Suzanne de la Monte
Our latest work shows increased brain cholesterol in AD. I don't know if this is caused by abnormalities in local insulin, but it may interfere with signaling. Maybe insulin sensitizers would be useful—peroxisome proliferator activated receptor (PPAR) agonists, for example (see ARF related news story on PPARγ agonists in AD).

Nancy Emerson
Other studies suggest the importance of docosahexaenoic acid (DHA) (omega 3-fatty acid) deficiencies and supplementation as important for AD pathology/treatment at least in transgenic mice (see ARF related news story). What are your thoughts on how polyunsaturated fatty acids (PUFAs) in brain cell membrane relate to action of insulin and IGF-1? You did show how the insulin/glucose metabolic impairments can be related to oxidative stress or extra vulnerability to oxidative stress.

Shaharyar Khan
Suzanne, why would the brain be reducing its insulin production at the same time as it's also reducing its insulin sensitivity by downregulation of insulin receptor signaling—if I understand the observations correctly?

Suzanne de la Monte
Maybe the cells that make the insulin also have receptors, or loss of insulin causes insulin-dependent neurons to die. We can't tell if individual neurons have lost receptors or insulin-receptor bearing cells have died.

Craig Atwood
Is it because there needs to be a balance between overall insulin signaling—if the receptor is decreased then you need less insulin?

Suzanne de la Monte
Not sure, Craig. If we deplete insulin receptors from the brain, we get neurodegeneration.

Craig Atwood
Yes, but if the insulin signaling remained high, you might get more—degeneration, that is.

Shaharyar Khan
Through desensitization?

Suzanne de la Monte
As a follow-up to my last comment, ethanol inhibits insulin receptor responsiveness and the neurons die, but the receptor number does not decline.

Shaharyar Khan
Through what mechanism?

Suzanne de la Monte
We have data that I hope will come out soon showing reduced insulin and IGF receptor responsiveness in AD, and associated loss of the receptors. I would think reduced growth factors would increase sensitivity, temporarily at least.

Marcos Marques
What is your hypothesis for the etiology of reduced neuronal insulin, IGF-1, and insulin receptor in AD cases?

Suzanne de la Monte
Marcos, that's a great question and I am looking at regular diabetes to try to understand why type II diabetes mellitus (DM-II) increases with aging. My guess is that there will be susceptibility polymorphisms in the brain.

Cyrus Raji
A growing number of papers over the past few years suggests that type II diabetics are at greater risk for getting AD due to impaired insulin degrading enzyme (IDE) function with respect to amyloid degradation. To Dr. de la Monte, how do you synthesize this knowledge with your own proposed mechanisms for the role of glucose and insulin in AD?

Craig Atwood
DM-II is primarily driven by obesity, no?

Cyrus Raji
 Correct.

Suzanne de la Monte
DM-II is insulin resistance, and some individuals are not obese at all—Asians, in particular, have this problem. A growing number of papers on this topic are very confusing. I am doing a systematic study of DM-II and brain pathology. As far as I can tell, there is no increase [in DM-II] in classical AD. Instead, there is substantial microvascular disease with white matter ischemia, which we already know contributes to AD. If there were IDE abnormalities, that would be interesting. We haven't found them, yet.

Craig Atwood
Agreed; you don't have to be obese, but at least have more fuel than the body can handle to store.

Cyrus Raji
As far as I know, only one study has examined AD pathology in postmortem diabetic brains. This was done at Albert Einstein College of Medicine in 1997 (see Heitner et al., 1997) and found nothing, but it was spotty because it included DM-I and DM-II samples. Does anyone know of any new work done in this area? My Medline searches have turned up nothing.

Suzanne de la Monte
The postmortem DM studies are horrible because they require medical input to clarify whether or not the original diagnoses were correct. Systematic study is now needed. We're trying, but other sites need to get involved.

June Kinoshita
Suzanne, are you talking about genetic studies looking at IDE?

Suzanne de la Monte
One other comment about IDE is that it would not explain mRNA problems.

June Kinoshita
Can you elaborate?

Suzanne de la Monte
We searched for abnormalities in IDE expression in AD brains and did not find them. IDE should degrade insulin polypeptide and as far as I know, has no impact on insulin gene expression. The mRNA levels for insulin are reduced [in AD brain]. If anything, degradation of a needed growth factor would lead to compensatory increased gene expression, not reduced.

Shaharyar Khan
Suzanne, I'm interested in the mitochondrial role in AD and diabetes—what, would you hypothesize would be the consequence of perturbed insulin signaling on mitochondrial function?

Suzanne de la Monte
Mitochondrial function is certainly abnormal in both DM-II and AD. It may be linked to insulin because insulin regulates mitochondrial function and oxidative metabolism.

Marcos Marques
Do you think infection or oxidative stress caused by a high carbohydrate diet may trigger an "immune" response causing all the insulin impairment in the brain?

Suzanne de la Monte
Marcos, I think stress can push the AD cascade over the line. I don't know about carbohydrate-rich diets, except they are possibly related to DM-II and microvascular disease.

June Kinoshita
Suzanne, by stress, do you mean oxidative?

Suzanne de la Monte
June, yes, ischemia, anesthesia, hypoxia. Not sure about life stresses—no epidemiological proof for a connection with AD or dementia.

Shaharyar Khan
Would you hypothesize that perturbed insulin signaling is capable of initiating the oxidative stress seen in AD? Do you see oxidative stress in, say, the insulin receptor substrate 2 (IRS2) knockout (KO) mice?

Suzanne de la Monte
Shaharyar, I think that is certainly one pathway that is operative. However, we are looking into the role of oxidative stress on insulin signaling. This could bring in the role of Aβ. IRS2 KO mice have increased glycogen synthase kinase-3β (GSK3β) activity (see ARF news story) on the link between GSK3β and the microtubule-binding protein tau, the major component of the neurofibrillary tangles found in AD brain). That would push the oxidative stress cascade.

Marcos Marques
What about stress mechanisms such as infection? Could they cause an autoimmune response that would deregulate insulin/receptors, etc., in AD brain?

Suzanne de la Monte
Marcos, that's interesting. Don't know the answer. What is your sense?

Shaharyar Khan
Many in the Aβ camp postulate that Aβ fails to be sufficiently degraded by IDE because IDE is possibly occupied by increased insulin, but you are finding that CNS insulin is actually down...meaning that if IDE levels were invariant, more amyloid ought to be degraded.

Suzanne de la Monte
Shaharyar, that's correct. I think we need to know more about IDE and its substrates. I still haven't given up because it may function differently in the presence or absence of Aβ.

Shaharyar Khan
Sure. Would you expect perturbed insulin signaling in familial AD (FAD) cases as you have seen in sporadic?

Craig Atwood
I wouldn't expect to see differences in insulin signaling in FAD.

June Kinoshita
Suzanne, Columbia University is embarking on a big epidemiological study of diabetes and AD. Over time, they will have individuals who come to autopsy.

Suzanne de la Monte
I think familial AD as well as Down syndrome should have the abnormalities in insulin signaling. Did you know there was an association between Down syndrome and DM? Can't find great references, but apparently there is.

Craig Atwood
 Why?

Suzanne de la Monte
Why not, Craig? The familial genes are not sufficient to trigger AD because the patients aren't born with AD; they must age or have something else happen.

Craig Atwood
But it could be any age-related hormonal change. Does insulin signaling change that much up to 40 years of age? That is, there are individuals with FAD before 40-45, but their insulin signaling is likely not changed.

Suzanne de la Monte
Insulin signaling certainly goes down with aging of the brain. Not sure about prior to 40. Good thing to check.

Shaharyar Khan
What would you suppose is the locus of the interaction for presenilins (PS), amyloid-β precursor protein (AβPP), insulin, and insulin receptor (IR)—maybe at the plasma membrane?

Suzanne de la Monte
AβPP and IR—plasma membrane. Not sure about PS.

Cyrus Raji
Dr. de la Monte, you said, I think, that you did not find altered IDE levels in the brains you looked at, but at least one study (Cook et al., 2003) suggests that hippocampal levels of IDE are reduced, although only in ApoE4 positive AD cases.

Nancy Emerson
A recent study, not published yet, at Veteran Affairs Medical Center, Bedford, with Richard Fine, J. Wells, and Pat Einenhauer, found abnormalities in IDE in epithelial (vascular) cells in human AD brain tissue samples.

Suzanne de la Monte
The IDE story needs sorting and more attention…that's clear.

Cyrus Raji
I agree with what Dr. de la Monte has said, and I think it is also important to be able to tease out the molecular mechanisms of vascular dementia vs. AD in DM-II and where the two may intersect, since this is a major point of confusion.

Marcos Marques
I believe it is quite possible we are dealing with an autoimmune disease. There is intense debate about infectious agents associated with AD. As for dietary impact, Lane and Farlow (see Lane, 2005) proposed that a Western diet may tip the balance toward fatty acid proinflammatory eicosanoids. They also observed that a high carbohydrate diet may increase insulin levels, increase insulin and insulin growth factor signaling, leading to a decrease in lipoprotein lipase activities that may trigger inefficient essential fatty acids to neurons that would inhibit glucose transport.

June Kinoshita
It would be worth looking at markers of insulin signaling in families with FAD mutations.

Suzanne de la Monte
We don't know that. We need to look at the impact of the genetic factors as an A+B story (two or three hits in the genome). How would we do this if the impairments are CNS and possibly not affecting the periphery? CSF could certainly help and could provide interesting information. PET scans to measure glucose utilization would also help.

June Kinoshita
Suzanne, what's on your wish list for how to push this area of inquiry forward? Access to certain reagents? Collaborations with people doing big DM-II studies, etc.?

Suzanne de la Monte
I think access to reagents and collaborations with other human investigators regarding DM and having brain tissue available would be great. We will be seeking NIH funding to do this type of work.

June Kinoshita
Do you have a list of candidate biomarkers in CSF of presymptomatic individuals that would be worth looking at?

Nancy Emerson
Suzanne, you probably know Florence Lai, a neurologist in the Boston area. She works with a largish group of people with Down syndrome and is an expert on AD in Down's. She is also leading international studies looking at vitamin E as a possible intervention to delay onset of AD in Down's. Perhaps she would be willing to collaborate with you. Also, please contact the researchers at the Veteran Affairs Medical Center (VAMC) Bedford doing the IDE work. We do have excellent access to brain tissue from the Boston University Alzheimer's Disease Center (BUADC). Neil Kowall is the principal investigator and also leads the New England Geriatric Research, Education, and Clinical Center (GRECC). He is a pathologist, as is his wife, Anne McGee. They would be interested in exploring this particular set of questions with you, I am almost sure. I'm willing to liaison if needed. We also have a new teammate, Wayne Matson, who does metabolomics and metabolic profiling from CNS, urine, and plasma that might be a part of the picture.

June Kinoshita
That's terrific, Nancy. Suzanne, what existing drugs, nutraceuticals, etc., would be interesting to study regarding effects on insulin signaling pathways and penetration across the blood-brain barrier?

Suzanne de la Monte
I would like to try insulin sensitizers directly in the CNS, and also agents that reduce membrane cholesterol in the CNS to improve ligand binding.

Marcos Marques
Did you study or plan to study mild cognitive impairment (MCI) cases? Or do you have any preliminary data on them?

Suzanne de la Monte
We have data on early AD—insulin abnormalities occur very early in disease. We have a paper in revision showing that Braak Stages I-II have impaired insulin signaling. Those patients have MCI.

June Kinoshita
Where does the impairment lie?

Suzanne de la Monte
The impairment exists in the hippocampus, hypothalamus, and frontal lobe. I think the basic problem stems from basal forebrain and cortico-limbic structures. This happens to be the distribution of insulin gene expression.

Nancy Emerson
Marilyn Albert says there seem to be two main types of MCI, those who progress to develop AD and those that remain abnormal but stable, cognitively. It would be interesting if it is the insulin signaling impairment that predicts progression. Have you explored this possibility? Right now the MCI folks do not know how to predict which will progress and which will not...and of course, knowing that is key to whether to intervene or not, especially if the treatment is non-benign.

June Kinoshita
That's an interesting idea, Nancy.

Suzanne de la Monte
MCI of the type that goes on [to develop AD] (like our postmortem cases) I would predict to have abnormalities in insulin signaling. Perhaps looking for this could help sort the problem clinically.

Marcos Marques
Interesting, in MCI cases, is the [insulin signaling] impairment worse or better than in AD? I am trying to make a longitudinal picture of this impairment. Would it be possible that this is a consequence of an exhaustion brain response to insulin?

June Kinoshita
What about a list of potential biomarkers related to defects in CNS insulin signaling? The Alzheimer Disease Neuroimaging Initiative (ADNI) study is going to be collecting biomarker data, and there are other collaborations looking at antecedent biomarkers, so these are important opportunities to include some novel candidate biomarkers (see ARF coverage of Mike Weiner's presentation on ADNI at the AD/PD meeting in Sorrento last March).

Suzanne de la Monte
Biomarkers...I'm not sure about which ones, yet!

June Kinoshita
Give it some thought and send me a list!

Nancy Emerson
One key challenge that Suzanne has pointed out repeatedly is the likely heterogeneity of the human cases we are looking at, and sometimes the confusion over the diagnoses, as well. That is why working with a larger AD center, with very careful clinical and postmortem diagnoses, will be important going forward for you, Suzanne.

June Kinoshita
Suzanne, you may have missed Nancy's offer to connect you with colleagues at Boston University who would be interested in collaborating.

Nancy Emerson
John Growdon at Massachusetts General Hospital now has the PET scan capability using the Pittsburgh compound (see ARF related news story on this imaging agent), so they can "see" changes in β amyloid deposition in vivo, e.g., in transgenic mice studies. Again, something that may be useful to you down the road. That, plus the imaging studies going on in New England and elsewhere.

Suzanne de la Monte
That would be great to be connected with the BU folks. I know John Growdon. I should try to talk him into looking at insulin and glucose utilization in relation to flow and acetylcholine.

Nancy Emerson
Okay, so maybe time to thank you Suzanne and wish you the best of luck in continued funding for your important research. I look forward to further chats with you about your work, findings, and theories, especially as related to intervention studies, both related to nutrition and physical exercise. As for Growdon, I am currently working a bit with him planning a conference on "Wellness for Persons with Dementia" happening this October. I have also been working on getting him more interested in the insulin resistance question. I wish he had had a chance to read your papers and be part of the chat. Maybe I will email him the pdf files. He is interested in Sam Sisodia's recently reported findings that transgenic mice bred to overexpress Aβ, living in enriched environments with more exercise and more cognitive/social stimulation have significantly less brain Aβ than litter mates in isolated regular cages (see Lazarov et al., 2005). I wonder if there is any connection to insulin signaling. Of course, these are TG mice and not human AD patients.

June Kinoshita
I'm afraid we are at the end of our hour, but I would encourage you all to continue this conversation offline. You can submit longer commentaries and questions that we can post on the Alzforum, and also explore possibilities for collaboration. Suzanne, thank you so much for leading this discussion.

Suzanne de la Monte
You're welcome. Thank you for the organization and help.

June Kinoshita
You're welcome. Goodbye, all!

Shaharyar Khan
Suzanne, thank you for the wonderful thoughts and work...I look forward to seeing your future endeavors (I especially liked your earlier work on mtDNA, hypoxia, etc., in AD). Thanks, all. Bye.

Craig Atwood
Bye; keep up the good work, Suzanne.

Nancy Emerson
Thank you! This was terrific.

Emory Hill
Thanks, all. A bit over my head, but I will follow the research by the names mentioned. I was here just to keep our related Web page up-to-date. Any feedback on the page would be appreciated.

 

Background

Background Text

This live discussion focuses on two articles appearing in the February 2005 issue of the Journal of Alzheimer's Disease, in which Suzanne de la Monte and her colleagues review a substantial body of evidence implicating reduced glucose utilization and defects in energy metabolism as an early and possibly causal event in Alzheimer's disease. The authors note that the diverse pathologies seen in AD, including Aβ deposition, neurofibrillary tangles, dystrophic neurites, cell loss, activation of cell death pathways, impaired energy metabolism and chronic oxidative stress, have been difficult to link together in a convincing framework. The authors hypothesize that defects in the central nervous system's own insulin and insulin-like growth factor signaling mechanisms play an early and central role, and provide a unifying explanation for the diverse and previously disconnected pathologies that characterize AD. They further argue that these defects are independent of peripheral mechanisms in diabetes mellitus, and therefore propose that AD may be viewed as a "type 3 diabetes".

Do you find the evidence solid, or are there important discrepancies with other data that need to be resolved? Is this hypothesis convincing, or are there other unifying viewpoints that you find more compelling? What exciting opportunities for new research does this hypothesis present? We urge Alzforum members to read the articles, and come with your questions, critiques and enthusiasms to join this provocative discussion. You can participate either by logging into the live chat on 25 March, or by posting questions and commentaries by email (send to junekino@alzforum.org). We thank IOS Press and The Gerontological Society of America for permission to provide full-text access to the following articles:

 

Steen E, Terry BM, J Rivera E, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease - is this type 3 diabetes? J Alzheimer's Dis. 2005 Feb;7(1):63-80. See full text (.pdf).

 

de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: Relevance to Alzheimer's disease. J Alzheimer's Dis. 2005 Feb;7(1):45-61. See full text (.pdf).

See also Addendum: Rasgon N, Jarvik L. Insulin resistance, affective disorders, and Alzheimer’s disease: review and hypothesis. J Gerontol A Biol Sci Med Sci. 2004;59A:178–183. Full text (.pdf).
Copyright © The Gerontological Society of America. Reproduced by permission of the publisher.

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Comments on this content

  1. My associates and I were originally exploring cholesterol depletion, and we kept running into the same compelling idea about oxidative stress in neurons. We published a review, which is referenced below.

    References:

    . Nutrition and Alzheimer's disease: the detrimental role of a high carbohydrate diet. Eur J Intern Med. 2011 Apr;22(2):134-40. PubMed.

References

Webinar Citations

  1. Is Alzheimer's a Type 3 Diabetes?

News Citations

  1. Outlook for PPARγ Agonists Not So Rosi
  2. Fish Oil Swims Ahead in Dietary Brain Protection Race
  3. Wingless Pathway Helps Tauopathy Take Off
  4. Sorrento: ADNI Imagines the Future of AD Imaging
  5. Sorrento: They’ve Just Got to Have It—Where’s That Biomarker? Part 2

Paper Citations

  1. . Diabetics do not have increased Alzheimer-type pathology compared with age-matched control subjects. A retrospective postmortem immunocytochemical and histofluorescent study. Neurology. 1997 Nov;49(5):1306-11. PubMed.
  2. . Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele. Am J Pathol. 2003 Jan;162(1):313-9. PubMed.
  3. . Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease. J Lipid Res. 2005 May;46(5):949-68. PubMed.
  4. . Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell. 2005 Mar 11;120(5):701-13. PubMed.

Other Citations

  1. junekino@alzforum.org

External Citations

  1. logging into the live chat
  2. IOS Press
  3. The Gerontological Society of America
  4. J Alzheimer's Dis.
  5. related Web page

Further Reading

Papers

  1. . Aspirin-like molecules that covalently inactivate cyclooxygenase-2. Science. 1998 May 22;280(5367):1268-70. PubMed.