Summary

Tobias Hartmann led this live discussion on 19 November 2002. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:

Live discussion held 19 November 2002. Led by Tobias Hartmann of the University of Heidelberg, Germany.

Participants: Gabrielle Strobel (ARF); Tobias Hartmann; Alexei Koudinov; Ben Wolozin; Weiming Xia; Detlef Schmicker; Gunter Eckert ; Gunnar Gouras; Claudia Almeida (Cornell Medical College, New York); Jim Brown (Loyola UMC in Maywood, Illinois); Reisuke Takahashi; Cassie Theisler (Maywood, Illinois); Frank Pfrieger; Christof Antz; Marcos A. Marques.

Gabrielle Strobel
Let's start, perhaps, with a basic question: Do people with AD generally have elevated plasma cholesterol, or are we talking about two different pools of cholesterol here, one central, one peripheral? Are we treating to lower neuronal- and glial-derived cholesterol?

Alexei Koudinov
I think that there are two pools that, of course, interact with each other. But how? Still remains to be investigated.

Tobias Hartmann
Well, certainly not everyone has high cholesterol; we see this in the studies. The idea is that it is high when deposition starts.

Ben Wolozin
My sense is that the linkage between serum cholesterol and AD is weak.

Tobias Hartmann
What we want to treat depends on opinion. I think one should treat neuronal cholesterol; Larry Sparks thinks that is dangerous and one should go for peripheral cholesterol lowering.

Gabrielle Strobel
Tobias, the increased CSF 24S-hydroxycholesterol that you measured in AD patients appears to be brain-derived cholesterol. Is more of it synthesized in the brain and transported out, or is there something wrong with its degradation?

Tobias Hartmann
We don't know this yet; my guess is that lipid homeostasis is altered the more you advance in the disease. That may be unrelated to the treatment.

Alexei Koudinov
Am I correct that while talking about 24S-OH cholesterol, we still are talking about its lipoprotein transport?

Ben Wolozin
Tobias and Alexei, people I have talked to, seem to feel that even though 24-OHC is referred to as "more soluble," it is still attached to lipoproteins such as ApoE.

Tobias Hartmann
24S is bound to proteins, like almost all lipids, it is not "freely" available.

Alexei Koudinov
What seems to be true is that even mild-to-moderate and chronic changes in systemic lipids (and cholesterol in particular) affect their brain pool.

Ben Wolozin
There is also the possibility that using statins to treat neuronal cholesterol gets at neuroinflammation and ApoE in the process.

Gabrielle Strobel
Ben, I am confused about the antiinflammatory connection: Statins are antiinflammatory, they reduce Aβ production, some NSAIDs are said to work by reducing Aβ production—that can't be all there is to it?

Tobias Hartmann
Ben, I agree again, [neuroinflammation and ApoE] may or may not be linked to Aβ.

Gabrielle, we definitely know that lowering cholesterol without statins or NSAIDS lowers Aβ.

Gunter Eckert
Tobias, to follow up on Gabrielle's point, cholesterol lowering [drugs] reduce Aβ in vitro, but the clinical studies failed to show an effect on AD progression for cholesterol lowering drugs other than statins.

Tobias Hartmann
Gunter, yes, I think this is an very important point—do you think because they are weaker? What do you think, Ben?

Ben Wolozin
Tobias and Gunter—yes, I agree that the only strong data is for statins. Although I never published it, I examined cholestyramine (which binds cholesterol in the gut) and it had no effect on AD, but the numbers were small.

Alexei Koudinov
Ben, some people in the lipid field (not neuroscience/AD) whom I talked to think lipoprotein transport is still involved in 24OH-cholesterol.

Ben Wolozin
Alexei—I agree that LP transport must be important.

Gabrielle, check out the recent paper in Nature showing protection by statins against experimental allergic encephalitis. While I strongly believe that statins are mainly affecting cholesterol in AD, there is clearly evidence that statins affect inflammation as well, and it would be unwise to ignore that angle.

Gabrielle Strobel
That's a mouse model for multiple sclerosis?

Ben Wolozin
 Yes.

Alexei Koudinov
Ben, the encephalitis story may refer to multiple sclerosis (MS) related models linked to myelin pathology.

Ben Wolozin
Alexei—yes, but immune driven. However, I do NOT want to steer this chat room towards inflammation! So, let's get back to cholesterol.

Alexei Koudinov
Ben, exactly, that's what I mean—with an immuno-related pathology.

I assume we all saw the recent Neurology paper by Fassbinder (Fassbinder et al., 2002) on no change in Aβ after statin treatment.

Tobias Hartmann
Alex, the Fassbender neurology study has one major problem: No AD patients and, importantly, no baseline samples. The (expected) small lowering of Aβ levels would not be detectable in such a study.

Gunter Eckert
Well, regarding the statins, I think that there must be a story behind lowering cholesterol; even the reduction of cholesterol is an important point.

Tobias Hartmann
Gunter, we should also keep in mind that Larry Refolo lowered aβ in mice without statins.

Gunter Eckert
Even in cell culture you need high statin concentrations to observe an effect on Aβ...

Alexei Koudinov
Gunter, that's what other people suggest, too (see the Neuroreport article by Yasojima et al.,2001).

Gunter Eckert
...also in the mice we needed big doses of statins to lower CNS cholesterol levels.

Ben Wolozin
It is important to note that Karen Duff used a different lipid lowering agent (in a Tg mouse model) and saw lowering of Aβ and a reduction in plaques.

Alexei Koudinov
...as well as Sparks' data on rabbits when Aβ fell after stopping the cholesterol diet (see Sparks,1996).

Gunter Eckert
Ben, you are right and this argues for a second effect of the statins in AD.

Tobias Hartmann
Gunter, Ben, probably all comes up to how long and how strong the treatment is. In humans treatment is long but at low concentrations. In animals it was just the opposite.

Gunter Eckert
Tobias, that is an important point and we have to keep in mind that the pharmacology in the animal model is quite different from humans.

Tobias Hartmann
Gunter, very [different].

Ben Wolozin
Gunter—do you think that ApoE is the main mechanism by which statins act on cholesterol in the brain?

Gunter Eckert
Ben if not the main, it definitely plays an important role, as we learned from our animal experiments.

Alexei Koudinov
Ben, I think many mechanisms are involved, all serving the maintenance of particular (i.e. very individual) cholesterol dynamics needs in the brain and brain regions.

Ben Wolozin
Alexei, then how do you account for the absence of an effect of lovastatin in Gunter's ApoE -/- mice?

Alexei Koudinov
I believe that there is a complicated interaction that is not limited to the brain tissue. It is possible that some systemic changes are mediated to the brain...causing some changes (or the lack of changes) that we can not explain yet.

Gabrielle Strobel
Tobias, I understand that in your pilot clinical trial, simvastatin reduced Aβ40 but not 42 in CSF? How do you interpret this?

Tobias Hartmann
Gabrielle, we saw the same decline but more variable. You can find it in the paper.

Gabrielle Strobel
In the trial, did you do cognitive tests, and did you see changes?

Tobias Hartmann
Gabrielle, I want first to bring in a word of caution. We did this clinical study but on purpose we call it a pilot study and we definitely want to see independent confirmation.

Actually, the pilot clinical study was designed as a proof of principle study: Are statins capable of lowering Aβ levels? It just turned out that there were also cognitive changes. We had not anticipated this originally and have not put in all thinkable power to address cognition. To me this remains an open question. There was an increase in MMSE but not ADAS-Cog.

Gabrielle Strobel
Tobias, is the CSF 24S-hydroxycholesterol elevation specific enough to be a biomarker, like phospho-tau appears to be shaping up? Is this worth pursuing?

Tobias Hartmann
Gabrielle, it is a good marker for the treatment, less good as a general marker for AD diagnosis.

Gunter Eckert
Regarding ApoE: There is no doubt that this apolipoprotein is one of the most important risk factors for the disease. The 4/4 [genotype] is strongly connected with AD. We now believe that this ApoE 4/4 is malfunctioning.

Ben Wolozin
Gunter, yes. Classically it is thought to increase Aβ aggregation, but to me it seems the fact that it is a risk factor for many types of neurodegeneration suggests that it might be operating through a mechanism more related to its cholesterol function.

Gunter Eckert
Ben, this in my impression too!

Knockout ApoE animals and animals that carry the human ApoE 4/4 show many similarities regarding parameters linked to brain cholesterol.

Ben Wolozin
Gunter—so are you saying that you don't think that ApoE has a strong effect on brain cholesterol? Gunter—what about plasticity (the classic meaningless catch-all term!!).

Gunter Eckert
Without question, ApoE is important especially for brain cholesterol metabolism.

Alexei Koudinov
Gunter, we have some related refs on ApoE4/cholesterol changes in ClinMed article accessible via our ARF hypothesis page. As for Ben's note, I agree with the primary importance of the ApoE allele for neurodegeneration through cholesterol dynamics (see previous ARF live discussion). For example—see Chapman et al.,2001 on role of ApoE in multiple sclerosis.

Gunter Eckert
Alexei, thanks I will have a look at it.

Ben Wolozin
Weiming—are you looking at cholesterol?

Weiming Xia
Ben, we have not looked at cholesterol, but are curious about Kovacs' findings on ACAT inhibitor effect.

Alexei Koudinov
Weiming, we have the letter commenting on Dora Kovacs' article published at British Med J.

Another thing I wanted to remind the audience about with special regard to Dora's comment on Tobias's background text for this discussion, that is a recent Neurology (2002) article (Gaist et al., 2002) reporting on polyneuropathy in statin users.

Tobias Hartmann
All, I think the mechanism of how cholesterol affects aβ production in cells is pretty much unresolved. I do not think that it directly interacts with the secretases, any opinions on this?

Ben, you think the a secretase effect is real or is of relevance in vivo?

Ben Wolozin
Tobias—I'm not sure. The fact that you see a lowering of Aβ is significant and implicates secretases, but doesn't prove it.

Weiming Xia
Tobias, I do not know if there is any direct effect on secretases. Bill Klein proposed its effect on a-secretase in 96, and later Urmoneit et al. talked about g-secretase. I do not see any more evidence showing up.

Gunter Eckert
Regarding the secretases we have to think about one factor: time...

Weiming Xia
If g-secretase cuts LRP, which binds ApoE, would this connect cholesterol to secretases?

Tobias Hartmann
Weiming, it makes a lot of sense for g secretase to be regulated this way. But then LRP is not only processed by g secretase.

Ben Wolozin
Weiming—wouldn't the g-secretase cleavage be constitutive?

Weiming Xia
Ben, it is no longer constitutive when you think of Aph-1 and Pen2, Nicastrin.

Tobias Hartmann
Ben, yes, g secretase is constitutive as far as we know. Maybe this is a challenge and Aph-1 etc. are also constitutive (until now).

Ben Wolozin
Weiming—true. I guess the question is how g-secretase affects trafficking of LRP, and whether this affects cholesterol. Any thoughts?

Gabrielle Strobel
Tobias, I understand that sorting and trafficking of cholesterol between different membrane compartments, and between membrane cholesterol and cholesterol ester pools, somehow affects APP processing. How could this work?

Tobias Hartmann
Gabrielle, this appears to be trafficking of secretase and substrate into the same compartment. The question is, why is γ-secretase in a very specific cholesterol sorting compartment?

Alexei Koudinov
Weiming, our referenced BMJ and other letters are accessible at our own web site.

Weiming Xia
Thanks, Alexei.

Tobias Hartmann
If we would find a true regulation for g-secretase activity, it may give us a lead to overproduction of aβ in AD.

Ben Wolozin
Weiming—any insights from your end?

Gabrielle Strobel
Gunter, where do the lipid rafts come in here? Do we know significantly more now to shed light on their role, other than that they contain the players of APP processing and high cholesterol?

Gunter Eckert
Gabrielle, I learned at the neuroscience 2002 that we should see the rafts in a more functional way—and this is only poorly understood yet.

Weiming Xia
Ben and Tobias, if indeed PS1 affects APP trafficking to the cell surface and re-internalization, similar effect could happen to LRP.

Tobias Hartmann
Weiming, …and cholesterol affects PS trafficking.

Ben Wolozin
To the group (since Dora isn't here): Any ideas why cholesterol esters would increase Aβ production?

Gabrielle Strobel
My thought exactly, Ben, thanks.

Alexei Koudinov
Ben, this question was puzzling me a year ago, and I guess I addressed it in the BMJ letter.

Gunter Eckert
Small changes in the composition, especially in cholesterol, in compartments hosting the secretases will lead to enhanced Aβ levels during the time.

Ben Wolozin
Gunter—but my understanding is that cholesterol esters are stored in special lipid compartments—which are different than where the β and γ-secretases are located.

Gunter Eckert
Ben that's true, I talked about unesterified cholesterol.

Tobias Hartmann
Ben, lipid droplets should be enzymatically inactive, but they still affect the total lipid homeostasis of a cell. But maybe, therefore, looking specifically on cholesterol and esters is misleading.

Gabrielle Strobel
Tobias, why is that misleading?

Tobias Hartmann
Gabrielle, because the active molecule may not be cholesterol but another lipid influenced by cholesterol levels or another protein.

Alexei Koudinov
My belief is that Aβ is involved in this interaction by modulating cellular/membrane cholesterol, so, both cholesterol and Aβ (and APP processing) affect each other. (See Michikawa et al.; Chochina et al.; and Koudinov et al.)

Tobias Hartmann
Alexei, I am waiting for experiments not using synthetic aβ, but cell- generated aβ, to prove this point.

Alexei Koudinov
I got your note, Tobias.

Ben Wolozin
Tobias—perhaps the accumulation of cholesterol esters in lipid droplets affects Aβ production indirectly, via feedback?

Tobias Hartmann
Ben, YES!

Gabrielle Strobel
In her comment, Dora Kovacs mentioned these alternatives to statins for cholesterol management: extended-release niacin, cholesterol absorption inhibitors, ACAT inhibitors, cholesteryl ester transfer protein (CETP) inhibitors. Do any of you know of their status?

Ben Wolozin
I have heard that niacin also lowers Aβ, but not as well as statins.

Tobias Hartmann
Gabrielle, I am afraid how long it will take before they can be used. But there is a lot of money in this for companies.

Tobias Hartmann
Ben, fascinating and these are less active in lowering cholesterol. Would make some sense.

Ben Wolozin
Yes, Gloria Vega in Texas has done this work.

Okay, so what else should we chat about?

Weiming Xia
Does niacin cross the blood brain barrier(BBB)?

Ben Wolozin
Weiming—I don't know.

Gabrielle Strobel
Since we have you here, Frank, let me ask everyone this question about synaptic dysfunction in early AD: Bill Mobley (Lynch et al.,2000) and you, Alexei (See Current Hypotheses), propose that AD results when disrupted cholesterol uptake and metabolism changes trafficking of membrane proteins needed for synaptic plasticity. This is also where perhaps altered APP processing would fit in. Since Frank Pfrieger showed that neurons need cholesterol and ApoE secreted from astrocytes, would this make AD a glial disease?

Alexei Koudinov
Gabrielle, thanks for this point. I submitted a comment on this matter. The idea is that synaptically released Aβ, and changed APP processing, may well fit the lipid-related function of Aβ (see links above) as was 'similarly' shown to other Apos, ApoE and ApoJ last year, by Horsburgh et al..

Tobias Hartmann
Frank, do you think statins could ever lower cholesterol in brain to a dangerous level before the other statin side effects set in? The clinical studies indicate that this is not possible in adult brain.

Weiming Xia
Tobias, if simvastatin is well tolerated in adult brain, it seems fine.

Ben Wolozin
Tobias there is a study from Finland showing that individuals with very low serum cholesterol are actually at increased risk for cognitive decline (presumably not due to AD!).

Tobias Hartmann
Ben, yes, but this is indicative not only of cholesterol but also a lot of other things, and they have lowered cholesterol also in the developing brain. And we know that cholesterol is very important in development and later cognitive decline.

Frank Pfrieger
Our hypothesis is that neurons shut down their cholesterol synthesis at least in the adult stage and depend on supply by astrocytes via lipoproteins. If true, then any interference with intercellular transport could cause problems. Lipoproteins bearing the ApoE4 allele may well be less capable of transporting cholesterol to neurons. Although I could imagine that other factors play a role. What I really wonder is whether Aβ interferes with the extracellular lipoprotein shuttle.

Alexei Koudinov
...regarding glial disease, I am not sure. Both glia and neurons tightly interact to do their job...Frank, we and others showed that Aβ affects cholesterol uptake by neural tissue (see refs above on lipid related function of Aβ).

Gabrielle Strobel
Alexei, I agree, I was being a bit facetious to stir things up...

Cassie Theisler
About the glial response, wouldn't one expect malfunction or changes (inflammatory responses) to occur in response to the disease state, how would you decipher which came first?

Alexei Koudinov
Ben/Tobias, and what about low cholesterol and increased suicide rate?

Ben Wolozin
Alexei—I think that there is no question that cholesterol has a huge impact on many factors in the brain. This is why the drug companies have focused on developing statins that don't impact on the brain (until they learned about AD).

Tobias Hartmann
Alexei, that has not been confirmed. But there is a higher violent death rate (murder), which I think was also not confirmed. I think this is a remote issue and I get depressed if I am not allowed to eat my burgers.

Ben Wolozin
Tobias—well, BSE will get you first then!

Gabrielle Strobel
Tobias, do you know why Bayer's statin was withdrawn? I've read mention in a press story about rare demyelinating side effects but probably there is more to this? Can you clarify rumors?

Tobias Hartmann
Gabrielle, the Bayer drug was withdrawn because Bayer could not stop the misuse (which they first propagated themselves).

Alexei Koudinov
Gabrielle, the drug withdrawal was based on a myopathy problem (Kind et al.,2002) that points to a special role for cholesterol at neuromuscular junction.

Weiming Xia
If atorvostatin does not cross the BBB, it may only reduce serum cholesterol without affecting brain cholesterol levels. Correct me if I am wrong.

Tobias Hartmann
Weiming, but how would it work in the brain, if it does not lower brain cholesterol....and if it does not enter the brain, it should also not be antiinflammatory in the brain.

Alexei Koudinov
Gabrielle/Frank, we think a bit different. We believe that lipoprotein transport is critical for fast delivery of cholesterol for short-term plasticity, while neuronal cholesterol synthesis serves long-term plasticity demands (see article in FASEBJ Koudinov et al.).

Gabrielle Strobel
Tobias, about the question whether statins that cross the BBB are more dangerous than those that don't. There must be voluminous records on the many thousands of people who have taken different statins for years. Do you know what they say?

Tobias Hartmann
Gabrielle, to the best of my knowledge, there is no relevant difference in the six different statins when it comes to side effects. Most big studies have been done with simvastatin.

Frank Pfrieger
Concerning the statin issue: The question is even for those that pass the blood-brain barrier how much actually enters the brain, since a certain fraction is absorbed by the liver.

Tobias Hartmann
Frank, correct, most of the statin stays outside the brain anyway.

Gabrielle Strobel
But then what do they act on, Tobias? Serum cholesterol? Astrocyte cholesterol? I am confused.

Tobias Hartmann
Gabrielle, neurons and astrocytes.

Gabrielle Strobel
We are nearing the end of the hour but you all can continue chatting for as long as you like (or until the burgers beckon to our European contingent, it's dinnertime there). Before people start leaving, let me thank everyone for coming today. This is an important topic and we will certainly follow up with another chat in a year or two.

Alexei Koudinov
Frank: ...I believe the statins that do not pass the blood brain barrier (but affect liver cholesterol status) also change brain cholesterol via yet not elucidated mechanisms.

Tobias Hartmann
Alexei, that is not what the FDA says.

Ben Wolozin
Tobias and Weiming—a vascular drug could affect cholesterol via ApoE.

Tobias Hartmann
Ben, that is a good experiment.

Weiming Xia
If we consider the hypothetic "drainage" model for the Aβ antibody vaccine, can cholesterol work in a similar way?

Tobias Hartmann
Weiming, nope, because hardly any aβ in plasma is produced in plasma. So I think this mechanism would not be affected by statins (as little as we know about this now).

Ben Wolozin
Weiming—I think the drainage model is a good point, except that I think many statins do not lower cholesterol in mice, but they do lower plaques.

Weiming Xia
We should have another discussion on CAA with passive vaccination.

Gabrielle Strobel
That is a great idea, Weiming. Would you please email me about it, gabrielle@alzforum.org, to help me plan it?

Alexei Koudinov
Weiming: ...this was a matter of AlzForum news some time ago...following a meeting report. See our comment on the ARF news item and its other comment.

Frank Pfrieger
The synthesis issue in neurons: In my opinion there are no convincing data yet showing cholesterol synthesis in neurons at the adult stage.

Gabrielle Strobel
What is the link between cholesterol and tau? Do not Niemann-Pick mice have neurofibrillary pathology?

Alexei Koudinov
Good we recall this subject. Yes, NPC mice has TAU changes, but Aβ changes, too.

Our explanation for tau changes is the one described in our last year study (see above for ref). We extended to hippocampal slices the cell culture findings of Fan et al. Furthermore, these data were further validated by several reports at the 31st SFN meeting '2001 in San Diego.

Gunter Eckert
Gabrielle, Fan et al. showed that mice develop NFT when they are treated with cholesterol lowering drugs.

Gabrielle Strobel
Gunter, why?

Gunter Eckert
Gabrielle, I do not know! But there must be a link.

Alexei Koudinov
I have an explanation why cholesterol depletion increase tau phoshorylation in hippocampal slices.

Gabrielle Strobel
Alexei, what did you find?

Tobias Hartmann
Gabrielle, a side pathway of the cholesterol biosynthetic pathway appears to be essential for this tau pathology. It is a study by Ohm.

Gabrielle Strobel
Right Tobias, I wish Thomas were here today.

Tobias Hartmann
When Ohm blocks specifically the geranyl/geranyl/pyrophosphate pathway, he gets alterations in tau phosphorylation. This is independent of cholesterol.

Gunter Eckert
Yes Tobias, that is the point!

Frank Pfrieger
Concerning the Fan et al. study as well as others: One possible reason may be the breakdown of axonal transport. As you may know, there is a paper from Klopfenstein et al. showing, with a clever in vitro assay, that kinesin-mediated transport of vesicles depends on a sufficient cholesterol level in the vesicle membrane.

Alexei Koudinov
...I think that tau changes are a more general reaction, not limited to the break in cholesterol dynamics.

We also have to remember that excessive tau phosphorylation occurs normally during early ontogenesis.

Gabrielle Strobel
Frank, can you provide a citation, or journal?

Frank Pfrieger
Avec plaisir: It's Klopfenstein et al., 2002, Role of phosphatidylinositol(4,5)bisphosphate organization in membrane transport by the Unc104 kinesin motor. Cell 109:347-358.

Alexei Koudinov
...recall PD, it also has tau changes in some cases, but we are not talking (yet, at least) about cholesterol changes there...so, I should get to the major point: As synaptic function is affected, neurofilaments change, and tau reacts. This was first suggested in 1991 by Perry et al. We further discuss it with relation to the break of plasticity due to cholesterol modulation in the FASEB J 2001 article (link is above).

Gabrielle Strobel
Many lines of evidence are converging on axonal transport these days, of APP, kinesin's role as APP receptor, tau elevation effect on inhibiting kinesin docking, now cholesterol
Tobias, what do you think of this?

Tobias Hartmann
Frank, Gabrielle, do you think cholesterol levels, as much as we can lower them in vivo, could affect axonal transport?

Gabrielle Strobel
Is there any way of finding out what the RIGHT cholesterol levels are in an adult human? Adult human brain, that is.

Tobias Hartmann
Gabrielle, I am not aware of a verified lower limit for plasma cholesterol, and I doubt this is known for brain.

Gunter Eckert
Regarding the RIGHT cholesterol concentration: We only have data from post mortem brain samples...and usually they are determined from brain homogenates.

 

Tobias Hartmann
Gunter, and this is?

Gunter Eckert
Definitely we could not learn so much from it.

Tobias Hartmann
Gunter, I agree postmortems tell us little what is causing the disease.

Gunter Eckert
Even because there are only marginal differences between tissue from AD and controls regarding cholesterol levels!

Alexei Koudinov
Gabrielle, we have a good ref at Noteworthy collection of the Neurobiology of Lipids: The importance of both actin and tubulin for the transport. It is a very recent article of just few days ago. The dynamics seem to be important.

Gunter Eckert
Alexei, that is also my point.

Alexei Koudinov
...that's where the study of the dynamics can show greater difference (if any).

Here is the ref I talked about: Dual control of caveolar membrane traffic by microtubules and the actin cytoskeleton. See Mundy DI et al., 2002).

Gabrielle Strobel
The key differences may be between a sick neuron and a nearby neuron that is still functioning okay, which you would never see with homogenates. Did cholesterol-related genes come up in studies of transcriptional profiling?

Alexei Koudinov
Gabrielle, you bring up an important issue: What is the sick state for a particular neuron? Is it constitutively sick due to genetics, dietary habits, or just because it needs extra cholesterol while building memories, or because it did not consume cholesterol (due to no activity) available to it?

Gabrielle Strobel
Alexei, I just mean that perhaps microarray studies of transcriptional changes of message amplified from very small samples, even individual postmortem cells, might point to differences in lipid metabolism in affected vs. still-healthy neurons..

Gunter Eckert
Alexei, these studies can show greater differences—also in post mortem brain samples from human (unpublished data).

Tobias Hartmann
There was an interesting poster by Mattson showing no difference in MCI but increasing differences the further AD progressed in various lipids, indicating that postmortems will show us the response to AD, not the cause.

Alexei Koudinov
Gabrielle, by the way, the genetics issue is covered in our Neurobiology of Lipids abstracts article Frankfurt, Germany Meeting (26 July 2002) on "Cholesterol and Alzheimer's". It is by Fabienne Wavrant-DeVrieze who works with J Hardy.

Gabrielle Strobel
Tobias, all, let me rock the boat a bit: Many researchers remain unconvinced that cholesterol and lipid homeostasis play a primary or early role in AD pathogenesis. They believe it is one of the innumerable things that are dysregulated as a consequence of the disease. What's the key, strongest evidence that makes cholesterol effects stand out?

Gabrielle Strobel
Tobias, but you think that elevated cholesterol is important presymptomatically, during midlife? Does this fit?

Tobias Hartmann
Gabrielle, as I said, cholesterol may not be the very molecule doing the trick. But the best point that lipids are very relevant for AD is that lipids are the only molecules (nonsynthetic, nontransgenic, but biological) that have profound effects on regulating aβ levels in both ways. Lipid levels vary from individual to individual, are taken up by diet, and are known to be influenced by many major and minor factors, like ApoE and others.

Frank Pfrieger
Gabrielle, I share your reservations. However, the fact is also that one of the major risk factors is ApoE4, and clearly one, if not the major function of this protein is to shuffle lipids around. So, I think lipids, at least including cholesterol, are in the boat!

Alexei Koudinov
Gabriele, I would make another statement: Cholesterol and other lipids are important as much as they construct neural membranes that maintain brain function. As the lipids change, the function change, and we then have Aβ, Tau and many other mechanisms launched to fix this.

Gunter EckertI
Alexei, let me add that cholesterol is the main modulator of membrane fluidity and this fluidity is important for all membrane related processes!

Alexei Koudinov
Exactly, Gunter, this is another possible mechanism to have the function affected and/or repaired.

Cholesterol change, of course, is just one of several possibilities likely important in AD.

Christoph Antz
Does AD correlate with other degenerative disorders like macular degeneration?

Tobias Hartmann
Christoph, AD correlates best with vascular dementia.

Gabrielle Strobel
I believe a majority of people with AD have some degree of vascular dementia. As a whole, the field seems to be at a loss for how to approach this experimentally?

Christoph Antz
I am Christof Antz and my father probably is developing some kind of dementia with possible macular degeneration in both eyes. I just was curious about the coincidence of both forms of degeneration.

Gabrielle Strobel
Chrisof, did you see the paper in PNAS recently saying that Aβ was detected in the Drusen of macular degeneration? I am not sure what this means, and it is to be replicated, but there you have a link...see Johnson et al., 2002.

Alexei Koudinov
Good point with vascular dementia. We have to talk about it and cholesterol, maybe in another session?

Christoph Antz
Thanks, Gabrielle. Does anybody know, if the "mouches volantes" that a lot of people over 40 are developing are probably Aβ deposits? I never saw an analysis of those floating peptides within the eye.

Alexei Koudinov
Thanks to Gabriele, June, and Nico, and of course to Tobias for organizing this session.

Tobias Hartmann
Okay, I think this was it. We should all stay in contact. Have a pleasant dinner and lunch with lots or little cholesterol, just as you like it.

Gabrielle Strobel
Good bye, everyone.

Background

Background Text
By Tobias Hartmann

When it comes to therapeutic issues in Alzheimer's disease, there is one theme everyone in the field is talking about these days, and that is cholesterol. This is astounding considering that just two years ago the issue interested very few scientists and before that time it was hardly recognized at all. This is not because there were too few publications; more than 200 papers addressed this matter in one way or another (to name a few key ones, see [1-7]). But not all articles were of desirable quality, perhaps important methods were not broadly available, and it seems that, overall, the field doubted that cholesterol was truly relevant for AD.

The pace picked up when, in October 2000, Wolozin et al.[8] showed drastically decreased prevalence of AD in former statin users and an independent confirmation appeared the next month. [9]. In May 2001, our group presented an apparent explanation for this finding: statin-dependent Aβ42 reduction in neuronal cell cultures and, importantly, markedly reduced Aβ42 levels in a guinea pig model Fassbender et al.[10]. That June, Kivipelto et al.[12] identified high midlife cholesterol as AD risk factor and in October, Refolo et al.[11] confirmed our finding by using AD transgenic mice. In March of 2002, our group linked cholesterol transport to presenilin localization and APP processing [13] and this past September, less then a year after the first in vivo statin data appeared, Simons et al.[14] showed in a small, prospective pilot trial that simvastatin indeed reduce cerebral Aβ levels in AD patients. Several larger, prospective trials are now ongoing or are slated to start this year.

We owe this fast progress not only to the scientists involved but also to a remarkable amalgam of helpful circumstances. Statins are very widely used in heart disease. This obviates the need to go through painstaking work identifying and modeling new suitable molecules; statins can be picked right off the shelf. Moreover, they have a benign toxicity profile hardly matched by any other major pharmaceutical. Numerous large statin trials have convincingly shown a beneficial outcome even independent of elevated cholesterol levels[15]. Since there is no reason to believe that statins interact with acetylcholinesterase inhibitors, accepted treatments need not be interrupted. The door to large prospective clinical trials is wide open. Moreover, AD research can dig into a wealth of data generated during the last decades by arteriosclerosis research and related fields.

How does it work?
The approach is simple. Statins inhibit the activity of HMG-CoA reductase, an essential enzyme in the cholesterol biosynthetic pathway. Lowered neuronal cholesterol levels result in reduced β- and γ-secretase activity, possibly further enhanced by increased α-secretase activity. The net effect of statin treatment would be similar to a combined β- and γ-secretase inhibitor treatment, plus the anti-inflammatory side effects of statins may come in as a welcome freebie. However, this is a very young field in AD research. The fast scientific progress has left many essential questions unanswered, some of which may contradict and complicate this simple scheme.

I suggest we discuss the pressing, unresolved issues below:

  • Vascular Dementia versus AD?
    The epidemiological data could be interpreted as a result of effects on vascular dementia. While the extent of overlap between vascular dementia and AD is a discussion topic by itself, there is general agreement that vascular dementia and AD often come together. Could it be that the positive outcome is due to a protective effect on vascular pathology and that the A benefit is just a welcome freebee? Moreover, high blood pressure also increases the risk for AD and vascular pathology[12]; does this indicate a vascular factor?

    Furthermore, inflammation has been a topic in AD research for some time. Statins have anti-inflammatory effects and this, too, may be related to vascular dementia. How important are the anti-inflammatory effects of statins? In-vitro and some in-vivo experiments show that the Aβ reduction by statins is dependent on cholesterol levels but independent of statin side effects. Even so, is this really the whole story?

     

  • BBB?
    How can we explain that statins believed not to cross the blood-brain-barrier (pravastatin) are apparently protective? Some even think that statins that do cross the BBB are dangerous. Why-because they would lower brain cholesterol too much?

     

  • Treatment or Prevention—Who Stands to Benefit the Most?
    High cholesterol levels during middle age appear to be an AD risk factor, but there is less agreement on cholesterol levels during clinical AD. If cholesterol does not participate in the disease process at this later disease stage, would statins be of use to AD patients or should they be used for prevention only? Is this issue the reason behind the finding in our pilot clinical study that patients might gain the most the earlier they are treated? Other treatment approaches, for example estrogen and NSAIDs, also wrestle with this issue of treatment versus prevention. How about sex differences? Bang from Suwon Korea reported in Orlando that only females, not males, of Tg2576 APP- transgenic mice reacted to high-dose lovastatin treatment with increased plaque formation. Male mice did not differ from controls at all.”

     

  • ApoE?
    ApoE4 is the best-validated genetic risk factor we know. Its role has been explained by a difference in Aβ clearance, fibrillization, or apoE-dependent repair processes. But apoE shuffles cholesterol between cells, and apoE4 differs from apoE3 in this respect. The link appears to be obvious, but Kivipelto [16] just reported that the ApoE4 and middle-age cholesterol risk are unrelated. See news .

     

  • Mechanism?
    Cholesterol levels affect secretase activity. But how this is done remains largely a mystery. Plenty of ideas are available, including an effect of cholesterol esters, but few hard facts are known. After all, why should the APP-degrading machinery be this sensitive to alterations in the lipid homeostasis? Furthermore, three different reports presented at the recent Society for Neuroscience meeting in Orlando indicate a role for ceramides and/or for gangliosides in Aβ production. It could be that the molecular mechanism actually works via one of these molecules rather than cholesterol. In this context, Luigi Puglielli in Dora Kovacs’ group suggested a second messenger- and senescence-related effect transmitted via ceramides rather than a direct lipid interaction effect.

     

  • Where is the link to Aβ42
    When numerous diverse AD mechanisms were studied in detail, sooner or later a specific link to Aβ42 was identified. Take NSAIDs, for example. Until now, no such link had been found for cholesterol. Is this because there is none, or didn't we look in the right places yet?

References

1. Bodovitz, S. and W.L. Klein, Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J-Biol-Chem, 1996. 271(8): p. 4436-40. Abstract

2. Sparks, D.L., Intraneuronal β-amyloid immunoreactivity in the CNS. Neurobiol Aging, 1996. 17(2): p. 291-9. Abstract

3. Kalmijn, S., L.J. Launer, A. Ott, J.C. Witteman, A. Hofman, and M.M. Breteler, Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol, 1997. 42(5): p. 776-82. Abstract

4. Liu, Y., D.A. Peterson, and D. Schubert, Amyloid β peptide alters intracellular vesicle trafficking and cholesterol homeostasis. Proc Natl Acad Sci U S A, 1998. 95(22): p. 13266-71. Abstract

5. Simons, M., P. Keller, B. De Strooper, K. Beyreuther, C.G. Dotti, and K. Simons, Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons. Proc Natl Acad Sci U S A, 1998. 95(11): p. 6460-4. Abstract

6. Frears, E.R., D.J. Stephens, C.E. Walters, H. Davies, and B.M. Austen, The role of cholesterol in the biosynthesis of β-amyloid. Neuroreport, 1999. 10(8): p. 1699-705. Abstract

7. Refolo, L.M., M.A. Pappolla, B. Malester, J. LaFrancois, T. Bryant-Thomas, R. Wang, G.S. Tint, K. Sambamurti, and K. Duff, Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis, 2000. 7(4): p. 321-31. Abstract

8. Wolozin, B., W. Kellman, P. Ruosseau, G.G. Celesia, and G. Siegel, Decreased prevalence of alzheimer disease associated with 3-hydroxy-3- methyglutaryl coenzyme A reductase inhibitors. Arch Neurol, 2000. 57(10): p. 1439-43. Abstract

9. Jick, H., G.L. Zornberg, S.S. Jick, S. Seshadri, and D.A. Drachman, Statins and the risk of dementia. Lancet, 2000. 356(9242): p. 1627-31. Abstract

10. Fassbender, F., M. Simons, C. Bergmann, M. Stroick, D. Lütjohann, P. Keller, H. Runz, S. Kühl, T. Bertsch, K. von Bergmann, M. Hennerici, K. Beyreuther, and T. Hartmann, Simvastatin strongly reduces Alzheimer's disease Aβ42 and Aβ40 levels in vitro and in vivo. Proc Natl Acad Sci U S A, 2001. 98(10): p. 5856-61. Abstract

11. Refolo, L.M., M.A. Pappolla, J. LaFrancois, B. Malester, S.D. Schmidt, T. Thomas-Bryant, G.S. Tint, R. Wang, M. Mercken, S.S. Petanceska, and K.E. Duff, A cholesterol-lowering drug reduces β-amyloid pathology in a transgenic mouse model of Alzheimer's disease. Neurobiol Dis, 2001. 8(5): p. 890-9. Abstract

12. Kivipelto, M., E.L. Helkala, M.P. Laakso, T. Hanninen, M. Hallikainen, K. Alhainen, H. Soininen, J. Tuomilehto, and A. Nissinen, Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. Bmj, 2001. 322(7300): p. 1447-51. Abstract

13. Runz, H., J. Rietdorf, I. Tomic, M. de Bernard, K. Beyreuther, R. Pepperkok, and T. Hartmann, Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells. J Neurosci, 2002. 22(5): p. 1679-89. Abstract

14. Simons, M., F. Schwarzler, D. Lutjohann, K. von Bergmann, K. Beyreuther, J. Dichgans, H. Wormstall, T. Hartmann, and J.B. Schulz, Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: A 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol, 2002. 52(3): p. 346-50. Abstract

15. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet, 2002. 360(9326): p. 7-22. Abstract

16. Kivipelto, M., E.L. Helkala, M.P. Laakso, T. Hanninen, M. Hallikainen, K. Alhainen, S. Iivonen, A. Mannermaa, J. Tuomilehto, A. Nissinen, and H. Soininen, Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med, 2002. 137(3): p. 149-55. Abstract

17. Puglielli, L., G. Konopka, E. Pack-Chung, L.A. Ingano, O. Berezovska, B.T. Hyman, T.Y. Chang, R.E. Tanzi, and D.M. Kovacs, Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid β-peptide. Nat Cell Biol, 2001. 3(10): p. 905-12. Abstract

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

  1. Failure of neural cholesterol dynamics is a primary pathogenic event in
    sporadic Alzheimer's disease

    In my view, the "How does it work?" scheme and "Mechanism?" question
    posed by Tobias Hartmann should be enhanced with the perspective presented
    in our FASEB article (1) and in the hypothesis posted earlier this year on
    Alzforum (2, see also 3-5). In brief, we believe that the fundamental
    pathophysiological event in most common sporadic forms of Alzheimer's
    disease is a failure of accurate brain cholesterol homeostasis. It is
    advocated by the fact that neuronal cholesterol pathology proper is a
    sufficient event to cause major Alzheimer's features of synaptic and
    behavioral impairment, amyloid formation, excessive tau phosphorylation,
    neurite degeneration, neuronal cell death, cholinergic dysfunction and
    oxidative stress. Details and complete bibliography are available at (2).

    References:
    1. Koudinov AR, Koudinova NV. Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. 15, 1858-1860 (2001),
    originally published online June 27, 2001, 10.1096/fj.00-0815fje Available
     at:

    2. Koudinov AR, Koudinova NV. Essential role for cholesterol in synaptic
    plasticity and neuronal degeneration.
    AlzForum: Hypothesis page. Posted
    online 19 August 2002. Available at:

    3. Simmonds MA. The emerging neurobiology of cholesterol. Neurobiology of
    Lipids Vol.1, 1 (2002) Published online August 30, 2002,

    4. Wood WG et al. Cholesterol and Alzheimer's disease. Neurobiology of
    Lipids Vol.1, 4 (2002) Published online August 30, 2002,

    5. Editorial material. 32nd Society for Neuroscience annual meeting
    neurobiology of lipids sessions. Neurobiology of Lipids Vol.1, 5 (2002)
    Published online September 23, 2002.

  2. Although statins may well be a godsend for patients with cardiovascular disease and perhaps Alzheimer's disease, the cholesterol management market is currently looking beyond statins. Why?

    One hard fact is that time is getting close for the expiration of statin patents, and this is rapidly diverting the interest of pharmaceutical and biotechnology companies toward alternative classes of lipid-regulating products. In addition, two scientific points should be considered. First, while it is true that the toxicity profile of statins is relatively benign in patients with high cholesterol, the efficacy of these compounds is not absolute, achieving the desired lipid-lowering effects in 80-90 percent of patients. Thus, 10-20 percent of patients still require alternative products to effectively manage their cholesterol. Second, statins specifically lower LDL levels, but have only modest effects on other lipids. An effective therapy for patients with low HDL, atherosclerosis, or other lipid disorders would ideally consist of a combination of lipid-regulating products (which could include but would not be limited to statins). Alternative products for cholesterol management so far include extended-release niacin, cholesterol absorption inhibitors, acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors, and cholesteryl ester transfer protein (CETP) inhibitors.

    While statins are already being considered potential therapeutic agents for the treatment of AD, the safety of these drugs for elderly patients with normal cholesterol has not yet been determined. Although only 1 or 2 percent of patients with high cholesterol levels present with serious adverse effects to statin treatment, large clinical trials are only now being carried out in elderly patients with normal cholesterol levels to assess the safety of these compounds for the prevention and treatment of AD. While awaiting the outcome of these trials, especially concerning the efficacy of statins in lowering Aβ levels, it would be prudent at this juncture to already start considering alternative therapies for managing lipids in AD patients. ACAT inhibitors were shown to lower Aβ production in cells (see news). As two ACAT inhibitors are currently in clinical trials for the treatment of atherosclerosis, this study promises hope for non-statin lipid management in AD patients. Most likely, other non-statin strategies for lowering cholesterol and Aβ will also be emerging over the coming years. Thus, the likelihood is quite high that cholesterol-based therapies for treating or preventing AD will ultimately involve a series of drugs to choose from, guided by the specific lipid management requirements in each patient.

  3. My associates were looking at cholesterol depletions and clinical effects of cholesterol loss from plasma membranes, and realized that the neuronal impact was huge. In a second review paper referenced below, we explored the implications of cholesterol depletion (as caused by glycation of ApoE in LDL) on membrane leakages and neuronal stress.

    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

News Citations

  1. Running the ApoE Marathon…
  2. Can Travel, Will Deposit: Aβ via the Perforant Pathway?
  3. Another Vaccination Approach, This One Against Cholesterol
  4. Mini-strokes from Passive Immunization?

Webinar Citations

  1. Cholesterol and Alzheimer's—Charging Fast But Still at a Distance from Solid Answers

Paper Citations

  1. . Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J Biol Chem. 1996 Feb;271(8):4436-40.
  2. . Intraneuronal beta-amyloid immunoreactivity in the CNS. Neurobiol Aging 1996 Mar-Apr;17(2):291-9. 1996 Mar;17(2):291-9.
  3. . Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol. 1997 Nov;42(5):776-82. PubMed.
  4. . Amyloid beta peptide alters intracellular vesicle trafficking and cholesterol homeostasis. Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13266-71. PubMed.
  5. . Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci U S A. 1998 May 26;95(11):6460-4. PubMed.
  6. . The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport. 1999 Jun 3;10(8):1699-705. PubMed.
  7. . Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000 Aug;7(4):321-31. PubMed.
  8. . Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000 Oct;57(10):1439-43. PubMed.
  9. . Statins and the risk of dementia. Lancet. 2000 Nov 11;356(9242):1627-31. PubMed.
  10. . Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5856-61. PubMed.
  11. . A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease. Neurobiol Dis. 2001 Oct;8(5):890-9. PubMed.
  12. . Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. BMJ. 2001 Jun 16;322(7300):1447-51. PubMed.
  13. . Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells. J Neurosci. 2002 Mar 1;22(5):1679-89. PubMed.
  14. . Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: A 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol. 2002 Sep;52(3):346-50. PubMed.
  15. . Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med. 2002 Aug 6;137(3):149-55. PubMed.
  16. . Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nat Cell Biol. 2001 Oct;3(10):905-12. PubMed.
  17. . Effects of statins on human cerebral cholesterol metabolism and secretion of Alzheimer amyloid peptide. Neurology. 2002 Oct 22;59(8):1257-8. PubMed.
  18. . 3-hydroxy-3-methylglutaryl-coenzyme A reductase mRNA in Alzheimer and control brain. Neuroreport. 2001 Sep 17;12(13):2935-8. PubMed.
  19. . Intraneuronal beta-amyloid immunoreactivity in the CNS. Neurobiol Aging. 1996 Mar-Apr;17(2):291-9. PubMed.
  20. . APOE genotype is a major predictor of long-term progression of disability in MS. Neurology. 2001 Feb 13;56(3):312-6. PubMed.
  21. . Statins and risk of polyneuropathy: a case-control study. Neurology. 2002 May 14;58(9):1333-7. PubMed.
  22. . A novel action of alzheimer's amyloid beta-protein (Abeta): oligomeric Abeta promotes lipid release. J Neurosci. 2001 Sep 15;21(18):7226-35. PubMed.
  23. . Amyloid beta-peptide1-40 increases neuronal membrane fluidity: role of cholesterol and brain region. J Lipid Res. 2001 Aug;42(8):1292-7. PubMed.
  24. . Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. 2001 Aug;15(10):1858-60. PubMed.
  25. . Comprehensive theory of Alzheimer's disease. The effects of cholesterol on membrane receptor trafficking. Ann N Y Acad Sci. 2000;924:104-11. PubMed.
  26. . Alterations in ApoE and ApoJ in relation to degeneration and regeneration in a mouse model of entorhinal cortex lesion. Exp Neurol. 2001 Jun;169(2):307-18. PubMed.
  27. . Rhabdomyolysis from the combination of a statin and gemfibrozil: an uncommon but serious adverse reaction. WMJ. 2002;101(7):53-6. PubMed.
  28. . Role of phosphatidylinositol(4,5)bisphosphate organization in membrane transport by the Unc104 kinesin motor. Cell. 2002 May 3;109(3):347-58. PubMed.
  29. . Neuropil threads of Alzheimer's disease show a marked alteration of the normal cytoskeleton. J Neurosci. 1991 Jun;11(6):1748-55. PubMed.
  30. . Induction and experience-dependent consolidation of stable long-term potentiation lasting months in the hippocampus. J Neurosci. 2002 Nov 1;22(21):9626-34. PubMed.
  31. . The Alzheimer's A beta -peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11830-5. PubMed.

Other Citations

  1. Tobias Hartmann

External Citations

  1. Abstract
  2. British Med J
  3. web site
  4. Koudinov et al.
  5. Neurobiology of Lipids

Further Reading

No Available Further Reading