Live Discussion: The Neuroplasticity Theory of Alzheimer's Disease
J. Wesson Ashford led this live discussion on 8 April 2002. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
View Transcript of Live Discussion — Posted 29 August 2006View Comments By:
Siegfried Hoyer — Posted 7 April 2002
By J. Wesson Ashford
The most fundamental statement about Alzheimer pathology is that it attacks
neuroplastic processes. At all system levels of function
(biological, psychological, social),
it is the capacity to store new information that is
affected by Alzheimer's disease. Tracing memory mechanisms to their most
basic levels leads to the loci at which Alzheimer pathology affects brain
mechanisms. This hypothesis was first proposed in 1985
(Ashford & Jarvik;
see Ashford, Mattson, Kumar, 1998, for full
discussion). This hypothesis has
recently been rediscovered, eloquently restated, and expanded by others
Arendt, 2001). This hypothesis has been
supported by repeated findings that pathological mechanisms associated with
Alzheimer's disease invariably end up being related to learning mechanisms
(e.g., acetylcholine, norepinephrine, serotonin pathways, NMDA receptors,
synapse counts, tau phosphorylation, Amyloid PreProtein, cerebral cholesterol
metabolism; see Ashford, Mattson, Kumar, 1998).
The neuroplasticity hypothesis also pulls together the tau and amyloid hypotheses with the corollary
hypothesis that there are two fundamental cellular memory mechanisms, each
attacked by one of two
types of pathology, the first by the amyloid (more closely linked to causation,
affecting more diffuse cortical regions including the temporal and parietal
lobes), resulting in senile plaques, then, once a critical
point is reached, the second by tau hyperphosphorylation, which leads to the
neurofibrillary pathology (correlated with dementia severity, initially affecting the
hippocampus and medial temporal lobe). In each case, if the delicate
balance between forming new connections and removing connections no longer
required is disrupted, Alzheimer pathology may develop. Amyloid PreProtein
processing tips away from an alpha-secretase/beta-secretase balance, to produce
excess beta-amyloid and resultant free-radicals. Tau is excessively
phosphorylated to the point that it forms neurofilaments, and then
neurofibrillary tangles. The neurofilaments appear to clog dendrite
(Ashford et al., 1998), which leads to amputation of the distal
portions of dendritic trees, large scale losses of synapses, and the increase
of CSF tau. These late changes correspond with the dementia severity
associated with Alzheimer's disease
(Ashford et al., 2001 for a
discussion of modeling of dementia severity.)
A central factor in Alzheimer's disease is ApolipoProteinE, which is produced
by glial cells and accounts for at least 50% of the Alzheimer's disease that
occurs between 60 - 80 years of age. APOE plays a central role in cerebral
cholesterol transport. Recent evidence has shown that cholesterol
metabolism is involved in neuroplasticity. Epidemiological studies are now
implicating cholesterol metabolism in Alzheimer causation. This chain of
causation provides yet another buttress to support the neuroplasticity
hypothesis of AD. Additional evidence suggests that cholesterol is
involved in Amyloid PreProtein processing, thus linking the APOE alleles to
amyloid production, thought to be central to AD causation, and further
supporting the role of this mechanism in neuroplasticity and the general
neuroplasticity theory of AD (
see Ashford and Mortimer debate position, in press,
for full discussion and references [.pdf file]).
Recent evidence supports the hypothesis that acetylcholine, a fundamental neurotransmitter
in neuroplasticity, inhibits both senile plaque and
neurofibrillary tangle formation (see figure adapted from Fisher, 2000).
This hypothesis suggests that drugs
which increase acetylcholine function, such as cholinesterase inhibitors, may slow or stop
Ashford, JW, Jarvik, KL. "Alzheimer's disease: does neuron plasticity
predispose to axonal neurofibrillary degeneration?" New England Journal of
Medicine. 5:388-389, 1985. Abstract
Ashford, JW, Mattson, M, Kumar, V. "Neurobiological Systems Disrupted by
Alzheimer's Disease and Molecular Biological Theories of Vulnerability." In:
Kumar, V. and Eisdorfer, C. (Eds.) Advances in the Diagnosis and
Treatment of Alzheimer's Disease. Springer Publishing Company: New York,
1998. Article [.pdf file]
Ashford JW, Soultanian NS, Zhang SX, Geddes JW. "Neuropil
threads are collinear with MAP2 immunostaining in neuronal dendrites of
Alzheimer brain." J Neuropathol Exp Neurol 57:972-8, 1998. Abstract
Ashford, JW, Schmitt, FA. "Modeling the time-course of alzheimer dementia."
Curr Psychiatry Rep. 3:20-8, 2001. Abstract
Debates on Alzheimer Theories: Cincinnati, July, 2001
Arendt T. "Alzheimer's disease as a disorder of mechanisms underlying structural brain
self-organization." Neuroscience. 2001;102(4):723-65. Abstract
Fisher, A. "Therapeutic strategies in Alzheimer's disease: M1 muscarinic agonists." Jpn J Pharmacol. 2000 Oct;84(2):101-12. Abstract
Mesulam MM. "A plasticity-based theory of the pathogenesis of Alzheimer's disease."
Ann N Y Acad Sci. 2000;924:42-52. Abstract
Live discussion held Tuesday, 8 April 2002
Participants: John Wesson Ashford (Wes), Bruce Teter, Kiminobu Sugaya, Suzanne Tyas, Keith Crutcher, Angele Parent, Bill Klein, Jacob Raber, Marsel Mesulam, Gabrielle Strobel, Alexei Koudinov, Pascale Lacor, Abraham Fisher.
Note: The transcript has been edited for clarity and accuracy.
Keith Crutcher: Hi Bruce!
Bruce Teter: Hi! Who else is here?
Kiminobu Sugaya: I am at the University of Illinois at Chicago, doing stem cell studies. Of course, I am interested in AD research
Suzanne Tyas: Hi, all. I'm an epidemiologist at the University of Kentucky. My research focuses on risk factors for Alzheimer's disease.
Bill Klein: Hi - I'm trying to eat sushi and type at the same time (beyond my skill level!)
Keith Crutcher: It would be interesting to have a discussion on the potential of stem cells for AD. Almost every news item on that story lists AD as a target.
Kiminobu Sugaya: I just came back from the Springfield/Geneva AD meeting in Switzerland. I talked about our stem cell study.
Keith Crutcher: Would the goal be to replace specific cell types or hope that cells will differentiate as they are needed?
Bruce Teter: Kiminobu - for stem cell target, what is "needed" - growth factors, neurotransmitters, etc?
Kiminobu Sugaya: Although some people were convinced by my presentation, others said we will never be able to replace neurons degenerating in AD brain.
Kiminobu Sugaya: Because, they said in AD, long cholinergic projection neurons cannot be replaced. I think it can be done. It's early days.
Keith Crutcher: There is precedence for transplantation of long-projecting neurons, namely dopamine neurons a la Anders Bjorklund's group.
Kiminobu Sugaya: Yes, that is why I said it can be done. On top of that, when we transplant the cells they migrate more than 1 cm in two weeks.
Jacob Raber: Is it not a general observation that the new cells may not easily obtain a neuronal phenotype?
Kiminobu Sugaya: In our case we saw a very nice neuronal morphology everywhere.
Bruce Teter: yes, replacing projecting neurons would be nearly ideal, but that hasn't stopped L-dopa treatment in PD or cholinesterase treatment in AD--seems like local effects can be somewhat therapeutic.
Keith Crutcher: Looks like we have a moderator....Hi Gabrielle!
Gabrielle: Hi Keith, hello and welcome to you all. I am Gabrielle Strobel, managing editor of the Alzheimer Research Forum.
Wes: Hi all.
Alexei Koudinov: Hello to everybody
Kiminobu Sugaya: Hi Wes, when you came to Chicago, you said long projecting neurons degenerating in AD can never be replaced.
Gabrielle: Hi Alexei, welcome, and hi Wes, guest of honor. Let's begin. Could you perhaps open the discussion, Wes, by restating briefly the key new developments that advance the neuroplasticity theory since we ran the interview with Dr. Mesulam? I will also throw out a question: according to the neuroplasticity theory, which is the earliest event that sets off the disease process in people without mutations in AβPP or presenilin?
Bruce Teter: Gabrielle's question on early events--if they are indeed synaptic loss as several reviewers have suggested--begs the question what causes synaptic loss, what are its signs, i.e. what markers can we look for early on?
Wes: Gabrielle, I would like to note that I did a search on neuroplasticity and Alzheimer on PubMed and actually found that Dr. Scheibel was credited with the first association. I made a statement in 1985 with Dr. Lissy Jarvik on the importance of plasticity, and I think that Marsel Mesulam's as well as Thomas Arendt's work reflect positively on that view.
Alexei Koudinov: Wes, I believe that earlier credit was associated with what we now call structural plasticity.
Kiminobu Sugaya: I would say adult neuronal plasticity is important in AD.
Alexei Koudinov: I would like to add that in my view the conclusions of both Siegfried Hoyer's pre-discussion comments (on insulin and cholesterol) could nicely add to our recent discussion on Alzheimer's vaccination, which was also about the rationale for tackling amyloid in AD.
Wes: I did want to respond to Dr. Hoyer's statements about insulin and metabolism. The earlier comments had to do with neuroplasticity in the sense that memories are laid down through the formation of new (structural) connections. But I think that the new statements only amplify the original ones by now showing what neurophysiological and neurochemical mechanisms are in play. It still seems that neuroplasticity relates to Alzheimer's disease at all levels, as was suggested before.
Alexei Koudinov: The plasticity as a way to fine-tune current neuronal/synaptic/field/etc action. I would like to add another background reference to the pre-discussion essay. That is Mesulam's article in
Wes: This citation is included in my statement, that is an excellent paper.
Gabrielle: Steve Paul's and Dave Holtzman's groups have a paper today reporting that a one-time injection of an Aβ antibody improves‚ overnight‚ the performance of old PDAPP mice in a memory and a learning task (see ARF news story). Bill, you noted a fast-acting effect of ADDLs in PNAS a few years ago. So do we have an immediate effect of soluble Aβ on synaptic function here? How would that work? Anyone?
Bill Klein: ADDLs have a selective impact on LTP that is quite fast (Wang et al 2002)!
We're very excited, by the way, about the results from Steve and Dave; they had mentioned them in the fall. They're in harmony with Dave Morgan's earlier studies in Nature that showed improvement by vaccination without much of an impact on amyloid deposits.
Gabrielle: That would strengthen a role for soluble Aβ directly on LTP. Any idea how that works?
Jacob Raber: Also fits nice with the growing evidence of cognitive deficits appearing before there are plaques.
Bill Klein: Here's a question -- how closely can we link mechanisms of functional and structural plasticity? If ADDLs block LTP, might they account for the structural synapse loss that Lennart Mucke reported in his amyloid-free mice (Mucke et al. 2000)
Keith Crutcher: I also would like to hear some discussion on this question of the precipitating events leading to AD. If we assume that the storage of new information (neuronal plasticity) is, by definition, required for memory, then dementia must involve a problem with plasticity. But isn't this a circular argument to some extent? Much as the definition that amyloid is critical to AD when its diagnosis requires the presence of amyloid plaques.
Alexei Koudinov: We also have to remember two 1995 articles that Aβ facilitates LTP (see e.g. Wu et al 1995), as well as several articles and meeting reports suggesting Aβ has a synaptic function rather than synaptic toxicity, as Selkoe's recent paper in Nature claims (see ARF news story).
Kiminobu Sugaya: Yep, I remember that. How about AβPP? Whenever neurons get damaged AβPP goes up
Wes: It still seems that Dr. Hoyer has not joined us, but he did append an elaborate statement to the original background text. His central issue is that the concept of plasticity leads to suggesting the systems in the brain affected by AD. However, Dr. Hoyer points to changes in metabolic functions. I believe that metabolic changes are secondary to the damage that is occurring to the neuronal processes. Regarding the vaccination issue, there is the fundamental problem of what normal role Aβ is playing in neuroplasticity, and that must be understood before trying to eliminate the substance immunologically. Good point, too, Alexei.
Angele Parent: Regarding fast-acting effect of antibody or Aβ, I would like to remind everybody that the plastic property of the synapse and associated memory process is intimately linked to the rapidity of synaptic response and remodeling.
Bill Klein: We think that it's possible to target (by vaccination) the nasty forms of Aβ, leaving behind the good Aβ (monomer). Vaccination with ADDLs gives the right type of antibody for this.
Jacob Raber: Why would monomeric Aβ not bind to the antibodies?
Bill Klein: Monomeric Aβ is "self" but assembled Aβ is "not self."
Kiminobu Sugaya: If the vaccination can destroy just Aβ deposition, it may be good.
I thought antibodies recognizing the n-terminal of Aβ eliminate Aβ deposition, but others do not.
Wes: Kimi, I think there is a balance between the alpha and beta secretases, perhaps controlled by acetylcholine. A critical problem may be what leads to the 1-42, rather than the 1-40 Aβ. That may be extremely important in view of Koo's work, as well as the statements from epidemiologists that NSAIDs greatly reduce AD risk. (Any comments, Suzanne?)
Suzanne Tyas: Wes, the epidemiologic studies do provide pretty consistent support of a protective role of NSAIDs in AD. Epidemiology is good at flagging these types of associations, then it's up to the basic scientists to work out the mechanisms!
Gabrielle: Last Thursday's paper by Dominic Walsh et al. reports he injected low-n Aβ oligomers into adult rat hippocampus and that inhibited LTP. They did this to advance their argument that Aβ oligomers are toxic to synaptic function. How does this fit with the neuroplasticity theory? Data by Angele suggests that PS-1 transgenic mice have higher LTP induction, not an inhibition.
Angele Parent: Our study was done in mice where bAPP was not overexpressed. So we cannot factor in the effect of Aβ.
Gabrielle: Angele, but they had a PS-1 mutation, right? Does not this mutation lead to overproduction of Aβ?
Angele Parent: Gabrielle, LTP in PS1-mutant mice can be completely independent of the presence of AβPP, since it appears that PS1 may by itself alter calcium homeostasis and other intracellular functions.
Kiminobu Sugaya: If just PS-1 mutation did not change LTP in mice, it means mice Aβ does not work? Why is everybody injecting human Aβ into rat or mice?
Wes: Suzanne, the issue is that certain NSAIDs may be preventing the toxic Aβ1-42. So, this may be a major direction for preventing AD. In light of the other on-going discussions, as there is a greater neuroplasticity burden (to use Dr. Mesulam's term), there would be more Aβ produced, and a greater risk of producing toxic Aβ. So the NSAIDs could really help in this way.
Bruce Teter: Wes, I see no evidence/mechanisms for NSAIDs directly affecting plasticity.
Wes: Bruce, the work of Koo suggests that certain NSAIDs may work by modulating gamma secretase activity, and so prevent Aβ1-42, which is presumably being produced excessively when there is a high neuroplasticity burden. (On NSAIDs in AD, see ARF news story, see ARF news story, see recent NSAID chat.)
Alexei Koudinov: As we switch often to vaccination I have to route you to our recent BMJ eLetter. My reference to Selkoe is indeed the reference to Walsh paper in Nature. Two co-authors of this paper are also the authors of 1995 papers on Aβ and synaptic plasticity that I referred to above. I am curious why they do not discuss their earlier finding that Aβ is improving LTP
Bill Klein: Alexei, they're probably now using the new improved Aβ.
Alexei Koudinov: Maybe, Bill.
Kiminobu Sugaya: Bill, what does "improved" mean?
Bill Klein: Kiminobu, sorry; kind of a joke.
Bill Klein: Anyone -- Is there any evidence that Aβ might build up first in a localized way, at synapses?
Bruce Teter: Bill, evidence - none I know of, but ideas of low-density lipoprotein receptor-related protein (LRP)-mediated uptake of Aβ at synapses are enticing. I think there might be some studies on synaptosomes and Aβ.
Alexei Koudinov: Bruce, I agree that Aβ may have synaptic relevance through the LRP. Importantly, apoE isoforms may provide the difference as pointed out by the associated difference with the pharmacological treatment with the different transmitter agonist. (Cedazo-Minguez et al 2001). There is a meeting report (Kamenetz, SNF 2000) and a paper (Huber et al., 1997) on an activity-dependent increase of synaptic AβPP, and a paper that Aβ upregulates synaptic protein transcript (Heese et al., 2001).
Gabrielle: Dr. Mesulam refers to an increasing‚ "physiological burden of neuroplasticity‚" with age. How does this fit with other studies that intense mental activity appears to protect from AD by creating a "cognitive reserve?" Does not mental activity create high demands, i.e. burden, on plasticity? You would think the most mentally versatile, active, changeable people would be "exhausted by the burden of plasticity‚" first? Instead, their plasticity seems to be best "trained‚" and thus protective. Am I getting this wrong?
Suzanne Tyas: Gabrielle, the issue of cognitive reserve strikes me too. One of the earliest and most consistent epidemiologic findings is the association between higher education and lower risk of Alzheimer's. Would more education reflect increased neuroplastic ability or increased burden?
Gabrielle: Suzanne, I would think both, and that is what puzzles me.
Wes: Gabrielle, this point of age and protection by use is very important and could make or break the theory. But, before looking at the question the way you have worded it, consider that early education is protective, that is, plasticity in the young individual. During that time, there are probably plenty of mechanisms protecting from AD. Later, those with greater reserves are able to solve problems using less cerebral metabolism, so are protected from such an excess burden.
Suzanne Tyas: Wes, the point about early education is interesting. Findings from the Nun Study showed a protective effect of education attained early in life. Further educational attainments acquired during adulthood were not significantly associated with subsequent risk of Alzheimer's.
Abraham Fisher: Hello to you all.
Gabrielle: Hello Dr. Fisher, and welcome!
Pascale Lacor: Kimi, did you ever see a change in dendritic spines in your AD model?
Kiminobu Sugaya: It is not an AD model. It is an amyloid model, and we have not checked spines in our animals in a specific manner.
Gabrielle: Is there any clear data on other molecular aspects of synaptic plasticity, for example mini-mRNA localization in dendritic spines, postsynaptic gene expression, etc, being affected directly by AD risk factors?
Pascale Lacor: Gabrielle, there is not much work on mRNA located at the dendritic spine and downregulated in AD models but it is time to look at that!
Kiminobu Sugaya: In our study AβPP increased stem cell differentiation. We have to check Aβ itself, though.
Jacob Raber: Soluble AβPPs?
Kiminobu Sugaya: Yes, soluble AβPP. Overexpression of AβPP by transgene did the same thing.
Alexei Koudinov: Soluble AβPP attenuated LTD (but enhanced LTP) in a paper by Mattson (
Ishida et al 1997)
Bill Klein: Alexei, interesting! ADDLs block LTP, not LTD, but LTD recovery is blocked, (Wang et al, 2002).
Alexei Koudinov: I also would like to address the earlier question on LTP and synaptic plasticity relation.
Bill Klein: Question -- what do you think of Barb Trommer's idea that a "shift" from LTP to LTD might lead to synaptic structural destabilization?
Alexei Koudinov: Important question, Bill. LTP and LTD are two different forms of synaptic plasticity. The lack of one (LTP) does not mean the gain of another (LTD).
Bill Klein: Alexei -- let me rephrase a bit. Since LTD is difficult to reverse in the presence of ADDLs, and LTP is blocked -- might this lead to structural destabilization, down-stream?
Alexei Koudinov: Bill - the change in both may have a structural basis.
Wes: Bill, Alexei, I am afraid my understanding of the precise mechanisms of LTP and LTD is not adequate to predict how each would fare in a brain being attacked by Alzheimer pathology. However, this is a central issue: Which of the two is attacked or are both? I would think that LTP would be a greater target, since that is the more human neuroplastic mechanism for making more widespread changes to store memories.
Gabrielle: Kimi, are you suggesting AβPP helps generate new neurons for plasticity and for replenishing dead ones in adulthood?
Kiminobu Sugaya: Gabrielle, yes in some sense. But at higher doses, it increases glial differentiation.
Pascale Lacor: Kimi, do you think, then, that AβPP is the receptor of something to target those new neurons?
Kiminobu Sugaya: I think it looks like a receptor, but our study indicates it is a messenger. I am proposing that AβPP is a signal from damaged neurons; it induces glial differentiation first and then causes neuronal differentiation as a result.
Pascale Lacor: Kimi, interesting.
Gabrielle: All who are interested in Kimi's differentiation data please note we are planning a live chat on AβPP function.
Abraham Fisher: Would anybody like to comment on the physiological role of Aβ? My hypothesis is that it is a regulating factor in muscarinic postsynaptic transmission.
Wes: Abe, welcome. I appreciate the article you sent me a year ago and hope my rendition on the web is satisfactory to you. Your paper suggests that acetylcholine, through the muscarinic path, has dual effects on reducing metabolic pathways leading to AD. I also believe that it is originally Dr. Mesulam's suggestion that the tauists and baptists could have their theories united by saying that each works on a related but separate aspect of neuroplasticity. Any comments?
Abraham Fisher: Wes, thank you. In fact I think that one has to be careful and not mix cholinesterase inhibitors with M1 agonists as far as AβPP processing is concerned
Kiminobu Sugaya: I also remind you AβPP has NPXY in its C-terminal, which is a DAβ1 binding site.
Wes: Kimi, your hypothesis that AβPP could serve as a signal to the glial cells is interesting, Clearly AβPP is going through either alpha or beta secretase pathways. There are several products from each. It seems that the alpha path would generate new synapses, while the beta path would lead to production of free radicals and eliminate synapses no longer needed. Clearly the glial cells would be involved in this.
Jacob Raber: Wes, the effects of AβPP and Aβ on glial cells might involve glutamate transporter activity.
Kiminobu Sugaya: Do cholinesterase inhibitors increase spine formation or protein synthesis in synapses?
Abraham Fisher: I know that ChE inhibitors can increase generation of AChE, but postsynaptically. This was shown both in preclinical and clinical studies
Pascale Lacor: NMDA is important for spine plasticity, does anybody know if acetylcholine is also a good "spiner"?
Bill Klein: General question: why does the cerebellum, which is relatively plastic, show minimal damage in AD?
Marsel Mesulam: Bill, structural plasticity might be identified by GAP43 and trkB expression. These markers are high in adult hippocampus but I do not believe they are high in cerebellum.
Alexei Koudinov: Bill, probably because cerebellum, as an evolutionarily older structure, has lower plasticity demands.
Abraham Fisher: How about the idea that the cerebellum is devoid of M1 receptors? If there are no such muscarinic receptors, vicious cycles that might involve it are not activated (Fisher et al 2000).
Kiminobu Sugaya: We recently checked cholinergic deficits in AβPP/PS-1 double transgenic mice, but we could not find much change in nucleus basalis of Meynert neurons, which provide major cholinergic input to the neocortex.
Bill Klein: All -- thanks!
Gabrielle: Does the neuroplasticity theory suggest a different approach to therapy/drug development from the ones currently pursued? Being perhaps more of a overarching concept, what can it contribute toward therapy development?
Abraham Fisher: I think this theory suggests that activation of M1 receptors is a viable therapeutic strategy.
Bruce Teter: Gabrielle, one therapy approach is to target the effects of apoE, which we have not gotten to yet, but this requires the additional complexity of pharmacogenomic approaches to apoE isotype-specific therapeutics.
Abraham Fisher: Regarding apoE therapy, do we need to increase apoE or decrease it?
Jacob Raber: Depends on the isoform.
Kiminobu Sugaya: Does that mean increase apoE2 and decrease E4?
Bruce Teter: Abee, apoE therapy would depend on your genotype, expecting that E4 should be decreased, while E3 or E2 increased, but this is simplistic. Thanks Jacob Raber - your fingers are faster.
Abraham Fisher: Bruce, Jacob, thanks. Bye to all.
Bill Klein: Bye to all... very much enjoyed chatting with you!
Kiminobu Sugaya: I would say do not alter physiological function of AβPP and Aβ. See you guys.
Marsel Mesulam: I enjoyed the discussion. Thank you.
Jacob Raber: Thanks to all.
Wes: Gabrielle, thank you for trying to get us to a cohesive view. I think that the neuroplasticity hypothesis suggests both where to look and how to understand the Alzheimer pathology. Then, anything that can affect those mechanisms is fair game for use in treatment. Abe is focusing on the M1 receptor, but it has been remarkable how much benefit the anti-acetylcholinesterase drugs are providing patients. We are currently saving the world billions of dollars, and more each year, through the use of these drugs. The next steps are to take the numerous other leads and put them together so that Alzheimer's disease is prevented. In each case, the effects of the drugs appear to relate back to neuroplasticity, and this hypothesis can be used to develop future therapies
Gabrielle: Intriguing pieces of an apparent connection between apoE4, cholesterol, and their effect on neuroplasticity keep cropping up, but I don't understand how the dots connect. How could this be made clearer?
Suzanne Tyas: Gabrielle, I agree that the connection with apoE, cholesterol and AD is unclear. The finding that high cholesterol may be beneficial in late life, in contrast to its detrimental effects on AD and other diseases in earlier life, is intriguing.
Keith Crutcher: Wes, you mentioned in your overview that apoE is critical for cerebral cholesterol transport. Do you have a reference for that?
Bruce Teter: Keith, I can provide you with references to recent reviews on CNS lipid metabolism.
Keith Crutcher: Thanks Bruce. I was wondering especially if the apoE-null mice have problems with cholesterol in brain.
Wes: Keith, I think that the apoE is another central issue here. The best discussion of the subject is in the discussion submitted by Rebeck, Kindy, and LaDu, which will appear in the July 2002 Journal of Alzheimer's Disease. One thing I believe is that the ApoE4 was the old version, the only version until 300,000 years ago, and the E3 and E2 subsequently appeared, basically, nature showing us one way to reduce or eliminate AD.
Keith Crutcher: Wes, I think it is an interesting observation but I have to confess that the idea of AD being a strong selective pressure is a bit of a stretch for me.
Alexei Koudinov: Unless we delete the nature effect with the new food era (see our above paper for some citations). By the way, we have in today's Neurology issue a contribution on cholesterol and Alzheimer's (Koudinov et al 2002)
Bruce Teter: Wes, Keith, evolutionary pressure of AD -I agree it is weak from our experimental biologist view, but something drove apoE evolution, although it may simply be diet, with AD being an unfortunate bystander.
Keith Crutcher: Bruce, that seems more reasonable...a pleiotropic effect.
Wes: I was just trying to make a summary statement, that we need to get Rebeck et al's review to clarify the relationship between cholesterol, apoE, and neuroplasticity. Also, regarding treatments, you can check my "top 10" at www.medafile.com.
Keith Crutcher: Wes, how about the issue of circularity in the neuroplasticity theory?
Wes: Keith, I myself have to circle out of here. I think that the issue of neuroplasticity is the central theme at all system levels. This goes more toward an all-encompassing theory. There are certainly many other theories that can be compared to neuroplasticity, such as free radicals, metabolism, aging, but none of these point to all of the changes in Alzheimer's disease at all system levels.
Bruce Teter: Wes, thanks for starting this discussion. Clearly a multifactorial issue requiring multitasking for this kind of discussion. I'll keep in touch.
Keith Crutcher: Wes, thanks for the time.
Wes: Thanks to all, bye.
Alexei Koudinov: Bye, and thanks for discussion. It is time for dinner here in the Middle East.
Gabrielle: This is a fascinating theory that provides a good umbrella for disparate lines of research. Thank you all for your time and thoughtfulness.
Kamenetz, F.R., Tomita, T., Borchelt, D.R., Sisodia, S.S., Iwatsubo, T., Malinow, R. Activity dependent secretion of b-amyloid: roles of b -amyloid in synaptic transmission. Soc Neurosci Abstr. 26, 491 (2000).
||Comments on Live Discussion
Comment by: Siegfried Hoyer
Submitted 7 April 2002
Posted 7 April 2002
|On Insulin and Neuronal Plasticity
Functionally, synaptic plasticity forms the most important site of neuronal plasticiy. Recent evidence suggests that both activity and plasticity of synapses depend on biochemical stimuli induced by the expression of the activity-regulated cytoskeleton-associated gene (ARC), which is regulated by the insulin/insulin receptor signal transduction cascade (Steward et al, 1998
; Zhao et al, 1999
; Guzowski et al, 2000
; Park, 2001
; Kremerskothen et al, 2001
Oxidative glucose metabolism, including ATP-production and acetylcholine formation in the brain, are controlled by insulin acting in the brain (for review see Hoyer, 2000a
Recent findings indicate that AbPP trafficking is under the control of insulin and the insulin receptor tyrosine kinase. Insulin increased dose-dependently the extracellular levels of AβPP, Aβ40 and Aβ42, and reduced the intracellular concentrations of all three AβPP derivatives (Solano et al, 2000; Gasparini et al, 2001). In all probability, cell cycle-associated enzymes and, consequently, cell cycle function in the brain, are under control of the insulin/insulin receptor (Conejo and Lorenzo, 2001; Conejo et al, 2001).
Figure 1 summarizes the normal function of the neuronal insulin/insulin receptor (I/IR)
- activation of oxidative energy metabolism
- maintains endoplasmatic reticulum (ER) / Golgi apparatus (GA) in maintaining a pH of 6
- activation of the S/G2/M phases of the cell cycle
- regulation of normal metabolism of both AβPP and tau protein (for review see Hoyer, 2000).
In sporadic Alzheimer's brain, both insulin concentration and activity of the insulin receptor tyrosine kinase are reduced. However, the density of the insulin receptor increases, indicating its upregulation and desensitization, similar to what happens in type II diabetes (Frohlich et al, 1998; Hoyer, 1998). As a consequence, a cascade of cellular and molecular abnormalities is set in motion, as summarized in Figure 2:
- the decrease in oxidative energy metabolism causes a deficit of ATP (Hoyer, 1992), which affects the ER/GA and protein trafficking (Verde et al, 1995),
- inhibition of the S/G2/M phases and activation of the G1-phase of the cell cycle (see above); a recent study on Alzheimer patients confirms signs of a G1 regulatory failure in lymphocytes (Nagy et al, 2002).
- abnormal metabolism of AβPP and tau protein.
Regarding AβPP, intraneuronal accumulation of Aβ42 leads to reduced concentrations in CSF (Tapiola et al, 2000), intracellular Ab42 is assumed to play a direct pathogenetic role in sporadic AD (Gouras et al, 2000). Tau, on the other hand, becomes hyperphosphorylated in ATP-deficient conditions (Röder and Ingram, 1991; Mandelkow et al., 1992; Bush et al, 1995).
In conclusion, the above data indicate that the amyloid cascade hypothesis is not valid for sporadic Alzheimer's disease, nor for disturbed neuroplasticity. Instead, we think the latter is initiated largely by a dysregulation of the neuronal insulin receptor.
On Cholesterol in AD
Intense discussion on the relationship between cholesterol and Aβ followed the publication of two retrospective clinical studies on a mixed dementia population (vascular dementia, sporadic Alzheimer dementia, secondary dementias) treated with statins (Jick et al, 2000; Wolozin et al, 2000) since the prevalence of dementia was reduced after treatment. Studies in cultured fetal hippocampal neurons and healthy adult guinea pigs, both treated with a statin in inadequately high dosages, resulted in a reduced formation of Aβ. T??? was interpreted as being beneficial for Alzheimer's disease (Simons et al, 1998).
Cholesterol is an essential sterol constituent of membranes and guarantees and stabilizes their function and structure. The neuron's capacity to form synapses depends on the availability of cholesterol, which is mainly provided by glia cells (see ARF news story). Intracellulary, cholesterol is formed from acetyl-CoA. Inhibition of its production decreased dendritic outgrowth and induced cell death (Michikawa and Yanagisawa, 1999; Fan et al., 2002).
Membranes in Alzheimer brains are severely damaged in their liquid composition, including cholesterol, which was demonstrated to be reduced in different brain areas (Svennerholm and Gottfries, 1994).
In postmortem Alzheimer brains, the unesterified cholesterol:phospholipid mole ratio decreased by 30 percent in the temporal gyrus. This lower membrane cholesterol content is assumed to cause an average 4A° (Angström) reduction in the lipid bilayer width, altering the biophysical properties of such damaged membranes (Mason et al, 1992). The reduction of cholesterol's cellular formation and membrane concentration in Alzheimer brains is mirrored by a decrease of cholesterol concentration in CSF (Mulder et al, Alzheimer Dis Ass Disord 1998; 12: 198-203). Destruction of cholesterol-rich cell membranes leads to a release of cholesterol from the brain in form of its derivative 24S-hydroxycholesterol in plasma and mainly in CSF (Lütjohann et al, 2000; Papassotiropoulos et al, 2002). This enhanced cholesterol efflux from the brain might follow an abnormal induction of the cholesterol-catabolic enzyme CYP 46 in glial cells (Bogdanovic 2001).
Since both Aβ40 and Aβ42 concentrations are reduced in the CSF during the spontaneus course of Alzheimer patients, and both cholesterol formation and concentration in Alzheimer brain are reduced in the disease process, there is no rational for a therapeutic strategy to reduce Aβ concentration via inhibition of cholesterol production by statins.
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