Live Discussion Transcript
Live Discussion Transcript
alzforum.org
Posted 28 August 2006
Live Discussion: Probing PPARã? Agonists: Could Diabetes Drugs Treat Alzheimer's Disease?
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Live Discussion held on 16 December 2002 with Elena Galea and Douglas Feinstein, University of Illinois, Chicago.
Participants: Gabrielle Strobel, ARF; June Kinoshita, ARF; Douglas Feinstein, UIC, Chicago; Gary Landreth, Case Western Reserve University, Cleveland, Ohio; Elena Galea, UIC, Chicago; Tilo Breidert, INSERM, Hopital Salpetriere, Paris; Donna McPhie, McLean Hospital, Belmont, Massachusetts; Rachael Neve, Harvard Medical School, Boston, Massachusetts; Leo Kesner, Dowstae Medical; Keith Crutcher, University of Cincinnati, Ohio; Michael Heneka, Bonn, Germany; Marykasch, Milwaukee, Wisconsin; Anindita Dutt, Mt. Sinai Medical Center, New York; Vitaliy Gavrilyuk, UIC; Detlef Schmicker, private interest, Duisburg, Germany.
June Kinoshita
Welcome to all. Thanks for showing up on such a snowy day (in Boston).
Gabrielle Strobel
Doug, Elena, and Gary, perhaps we can start this off with a brief reminder to all here (and the readership of the transcript) how nonsteroidal antiinflammatory drugs (NSAIDs) affect peroxisome proliferator-activated receptor-ã (PPARg) pathways. I think that is one angle by which the field can connect PPARg to Alzheimer's disease (AD).
Douglas Feinstein
Well, the key finding was made by Lehmann et al. that NSAIDs activate PPARg.
Gary Landreth
The primary finding that drove the interest in PPARg in AD arose from findings by Lehmann showing a subset of NSAIDs bound to and activated PPARg. The principal mechanisms relevant to AD center on the ability of PPARg activation to transcriptionally transrepress proinflammatory gene expression.
Douglas Feinstein
They also showed that the NSAIDs activated PPARg at millimolar levels, versus the micromolar levels which inhibit cyclooxygenase (COX).
Rachael Neve
Gary, I think that the other critical information about PPARg is that it also affects the cell cycle, which is disrupted in AD.
Douglas Feinstein
Also, as I recall, they showed specificity in activating PPARg, as opposed to the other PPARs (a and d).
Gabrielle Strobel
Rachael and Donna, I found your Neuroscience abstract showing that PPARg agonists specifically blocked the apoptosis induced by FAD-APP mutations in cultured primary cortical neurons very interesting. What agonists did you use?
Donna McPhie
We used rosiglitazone and GW1929.
Tilo Breidert
Was rosiglitazone used in vivo?
Rachael Neve
Tilo, our lab didn't use it in vivo. We have shown that expression of familial Alzheimer's disease (FAD) amyloid-b precursor proteins (AbPPs) in primary neurons in culture causes DNA synthesis to occur. PPARg agonists block this synthesis. So that's another effect of PPARg that needs to be taken into consideration, besides its antiinflammatory effects.
Elena Galea
Gary and Doug, we move to the question, in the animal models of AbPP what effect of ibuprofen do you think may be mediated by PPARs?
Douglas Feinstein
Well, for example, clearly some antiinflammatory effects of ibuprofen can be replicated by PPARg selective agonists.
Gary Landreth
In the AbPP models it is not clear to what degree the effects are PPARg-mediated as opposed to being mediated by non-receptor mechanisms. In the absence of good antagonists that work in vivo, it is difficult to say. Clearly, the ibuprofen effects on Ab42 are not PPARg dependent.
Gabrielle Strobel
All, do you think the role of PPARg pathways in inflammation and in the cell cycle entry/apoptosis triggered by FAD AbPP are connected? What could be going on here?
Gary Landreth
The antiinflammatory actions we have seen in the V717I and Tg2576 mouse models may well be due to PPARg; however, clearly other mechanisms are in play.
Douglas Feinstein
Donna, Rachael, I'm sure you're familiar with the reports of PPARg agonists inducing apoptosis, particularly in tumor cell lines.
Donna McPhie
Yes, but the tumor cell lines are dividing cells.
Rachael Neve
Yes, Doug, we're familiar with that literature. We find that many agents that cause apoptosis in dividing cells PREVENT it in neurons, and that seems to be the case with PPARg agonists. By the way, does anybody have any PPARg agonists that cross the blood-brain barrier? We've been looking for one.
Douglas Feinstein
Donna, yes, which is perhaps why they enter apoptosis, versus effects on neurons. Rachel, to my knowledge (limited), the only agonist that has been shown to cross BBB is pioglitazone.
Gabrielle Strobel
Rachael, I thought pioglitazone does. No, Elena?
Elena Galea
Yes it does, not rosiglitazone, right Gary? Didn't you have some evidence about that?
Douglas Feinstein
Although Jill Richardson may have shown that ciglitazone does as well?
Tilo Breidert
Rachael, Doug, the permeability is rather low, but it crosses the BBB (Meashiba et al.).
Gary Landreth
Ciglitazone and pioglitazone pass the BBB. Rosiglitazone does not.
Rachael Neve
What's the specificity of pioglitazone? Is it highly specific, or does it have other effects as well?
Elena Galea
Rachael, that is the whole point, the target of pioglitazone is not clear.
Douglas Feinstein
Pioglitazone is about 10-50 fold specific for PPARg versus other PPARs. All thiazolidinediones (TZDs) have other effects.
Elena Galea
But we did not find PPARg in the brain....
Rachael Neve
We found PPARg in neurons.
Gary Landreth
The only data on BBB permeability is contained within a paper on pioglitazone published by a Japanese group in 1997. Jill Richardson at Glaxo has looked at a subset of TZD and non-TZD agonists, though this data is not in the public domain.
Douglas Feinstein
She did present the data, however, at meetings.
Elena Galea
Rachael, cell cultures and whole brain may be different. PPARg is also expressed in cultured astrocytes.
Tilo Breidert
Elena, PPARs in astrocyte: reference Cristiano et al., J Neurocytology.
Rachael Neve
Donna, did we ever check for PPARg in brain tissue?
Donna McPhie
No, we haven't checked brain tissue.
Rachael Neve
Clearly that's an important experiment to do, to see if we replicate Elena's finding that PPARg is not in the brain.
Tilo Breidert
Rachael, yes we did. There is very weak expression in brain lysates (compared to adipose tissue, for example).
Rachael Neve
Oh, that's encouraging, Tilo, that you find expression in brain lysates, albeit weak.
Tilo Breidert
See our J Neurochem article.
Gary Landreth
We have looked in rat brain for PPARg expression. Endogenous levels of the receptor are quite low but detectable. There is published RT-PCR data on all three isoforms.
Douglas Feinstein
The group in Lausanne (Wahli, Braissant) published early on, that PPARs are in brain, including PPARg.
Tilo Breidert
Rachael: PPARg mRNA levels were measured by Escher et al.
Douglas Feinstein
With regard to the BBB, in cases of multiple sclerosis, stroke, and perhaps AD (?), the disruption of BBB may allow entry into damaged areas.
Rachael Neve
That's an interesting point, Doug, that the integrity of the BBB may be disrupted in AD, allowing entry into damaged areas.
Gary Landreth
We find PPARg expression is elevated in the penumbra following ischemic stroke in rats.
Douglas Feinstein
Another consideration is whether PPARg is upregulated in disease? It is upregulated in activated T cells versus normal T cells, for example.
Rachael Neve
Has anyone checked for upregulation of PPARg in AD brain?
Douglas Feinstein
Rachael, there's one paper by Kitamura showing increased PPARg in AD.
Gabrielle Strobel
Tilo, are PPARg agonist drugs being tested in PD?
Tilo Breidert
No, not to my knowledge.
Gabrielle Strobel
Are the companies selling pioglitazone and rosiglitazone not testing the drugs for AD?
Douglas Feinstein
Re company testing... unfortunately we have no one here from Takeda or Glaxo to answer that.
Elena Galea
Two points: 1. Are the levels of PPARg sufficient to make an effect? 2. Jill Richardson from Glaxo showed that the antiinflammatory effect is receptor independent.
Rachael Neve
We've shown that the effects on PPARg agonists on neuronal DNA synthesis and apoptosis are most decidedly receptor dependent. We've also shown that, although COX-2 inhibitors have a small effect on neuronal DNA synthesis and apoptosis caused by FAD AbPPs, that effect is abrogated by PPARg antagonists.
Gary Landreth
Elena, the issue of to what degree the antiinflammatory effects on gene expression are mediated through PPARg is complicated, and the experimental outcomes frequently depend upon the cell type and the inducing stimulus. It should be noted that the original report from Jiang/Ricote showed that LPS-driven cytokine expression was unaffected by PPARg agonists whereas phorbol ester stimulated responses were suppressed. These and subsequent data support the view that the susceptibility to inhibition by PPARg activation is dependent upon how the promoters of the proinflammatory genes are loaded.
June Kinoshita
Re: PPARg in brain, is it known whether the expression is neuronal or glial? Any data on regional specificity?
Elena Galea
June, in normal brains we do not see much staining, in ischemia PPAR is neuronal.
Tilo Breidert
June: Cristiano et al., shows PPARg in cultured astrocytes; by personal communication I was told that in vivo [it is expressed] in astrocytes too.
June Kinoshita
Thanks, Elena and Tilo.
Gabrielle Strobel
Re company testing: Donna and Rachael, did you collaborate with people from Glaxo in your study? Do you know anything of their interest in AD for rosiglitazone?
Rachael Neve
Yes, we collaborated with Tim Willson at Glaxo. He is interested in PPARg agonists for AD and is trying to get a good agonists that passes the BBB.
Douglas Feinstein
Rachael, Donna... there's an interesting article showing that low doses of pioglitazone are protective against apoptosis, in receptor independent and dependent manners.
Rachael Neve
Doug, do you remember who wrote that article?
Douglas Feinstein
Rachael, no, I will find out....
Gabrielle Strobel
With the NSAID-Ab connection, one concern is that doses needed for Ab reduction may be too high to be safe for chronic use. Gary, can you see this dose problem coming up with the use of TDZ drugs in AD, as well?
Rachael Neve
Gabrielle, it depends on whether you are interested in Ab reduction or not. We are more interested in inhibition of cell cycle and apoptosis; very low doses are adequate for that effect.
Gary Landreth
Gabrielle, the ibuprofen doses used by Golde, Koo, and Lim, are at the upper reaches of clinically acceptable levels in humans. The effects we have observed in mice with pioglitazone are well above FDA-approved levels.
Douglas Feinstein
The dosing for TZDs in humans for type 2 diabetes was established so that 45 mg/day gave optimum insulin sensitizing effects with no apparent side effects. I'm not sure if they ever tested safety at higher doses of pioglitazone or rosiglitazone.
June Kinoshita
Tuck Finch, and no doubt others, have suggested that the AD-protective effects of NSAIDS may be as a result of the drugs' effects in the periphery, rather than in the CNS.
Elena Galea
June, what is the peripheral mechanism they propose?
June Kinoshita
Elena, that's an open question, but I think it's assumed that it has to do with peripheral inflammatory mechanisms. But it's worth thinking about other possibilities.
Elena Galea
June, this is the case of rosiglitazone being protective in AD that Suzanne Craft has shown some preliminary data on.
Douglas Feinstein
The data from S. Craft is quite interesting.... How good is that data (i.e. rosiglitazone improves cognition in AD?
Gabrielle Strobel
Doug: I think rosiglitazone improved performance in a test of verbal memory but not other tests in a small pilot trial.
Gary Landreth
Doug, the data from S. Craft are on 10 AD and five control patients on rosiglitazone. She reported data following four months of treatment. There were statistically significant changes in paragraph recall and a measure of attention.
Rachael Neve
Yes, that's always been a puzzle, that NSAIDS don't cross the BBB and yet seem to have this protective effect.
Elena Galea
Rachael, ibuprofen crosses the BBB.
Rachael Neve
Elena, I didn't know that! Obviously there's a huge gap in my knowledge.
Michael Heneka
There are good data for ibuprofen crossing the BBB (Bayer Pharma Patents).
Douglas Feinstein
Gary, have you tested any higher doses in mice or rats (higher than the 100 ppm).
Gary Landreth
Doug, we have looked at pioglitazone at 120 ppm in a study with Martin Citron at Amgen, and did not see any antiinflammatory actions in the TG2576 mouse. In a second study with Michael Heneka and Fred van Leuven we used a dose of 240 ppm and saw nice antiinflammatory effects.
Rachael Neve
Do other NSAIDs (like indomethacin, naprosyn) cross the BBB? I'm also interested in how you do the in vivo dosing, those of you who have experience with it. Don't the animals have GI problems? Do you introduce it some way other than orally?
June Kinoshita
Elena and Michael, do you know what concentration ibuprofen would be at in the brain if given at doses that are supposed to be protective (in epidemiological studies)?
Michael Heneka
June, if my memory serves me right more than 40 percent of ibuprofen will cross....
Douglas Feinstein
One of the problems with the TZDs is not the GI, but increased edema.
Rachael Neve
Yes, Douglas, but how about NSAIDs?
Douglas Feinstein
Rachael... in our limited studies using ibuprofen (orally) we saw no effects on edema, didn't check for GI.
Michael Heneka
Doug, we did not observe any edema in the animals treated even when we were looking carefully for any changes.
Douglas Feinstein
Michael, you should see our EAE mice... significant edema, but perhaps this is a T-cell response.
Vitaliy Gavrilyuk
Michael, Doug is right, there is an edema when using some of TZDs.
Michael Heneka
Where did you see the edema? Did you check for other reasons/infections etc. PPARg makes [animals] more susceptible to infections anyway....
Elena Galea
Pierre, can you describe the effect we saw on pioglitazone and ventricule size.
Elena Galea
Pierre is gone. We saw that a two month-treatment with pioglitazone increases the size of ventricules in B6 mice, indicating that pioglitazone is altering the flow of CSF, which may explain the increase in water retention and edema.
Gabrielle Strobel
June and Elena, I was going to ask Suzanne how she explains her effect of rosiglitazone on memory tests. Too bad she could not make it. This brings up another question to all: Could there be other connections between metabolic disease and AD that the PPARg agonists could be hitting simultaneously? I am thinking of a link between atherosclerosis and diabetes and breaches of the blood-brain barrier.
Elena Galea
Gabrielle, I cannot speak for Suzanne, but they seem to think that rosiglitazone increases the effect of insulin in the brain. They have shown previously that hyperinsulinemia improves cognition in AD patients. The mechanism is not clear. Since rosiglitazone does not cross the BBB, it is not acting directly on hippocampal neurons, for instance. One possibility is that it is acting indirectly, by stimulating neuronal pathways in BBB-devoid areas, like the hypothalamus.
Gary Landreth
Elena, the mechanisms underlying Craft's effect are unclear to me and there are a number of possibilities. We have applied for funding for a FDG-PET study to look at 20 patients on pioglitazone and establish whether their is a metabolic consequence of PPARg administration in the brain.
Douglas Feinstein
Gabrielle, did she do those studies under maintained glucose levels? i.e. or were blood glucose levels increased as well?
Dutt
If I may ask, is the rosiglitazone action due to altered insulin sensitivity or some other pathway...?
Douglas Feinstein
Dutt, rosiglitazone is the highest affinity PPARg agonist (about 10 fold higher than pioglitazone).
Elena Galea
An interesting possibility for rosiglitazone, is that by stimulating the HPA axis, an area rich in insulin receptors, it may stimulate the locus coeruleus, which is an area of projection of the hypothalamus. This would lead to the production of noradrenaline, which we know is antiinflammatory and its levels are reduced in AD.
Gabrielle Strobel
Gary, you are about to start a pilot trial with pioglitazone? It is interesting that NIA decided to fund it even though there is no prior epidemiology, as there was for clinical trials of NSAIDs, statins, and estrogen for that matter. Do you want to tell us more about this upcoming trial?
Gary Landreth
Gabrielle, we have initiated a pilot clinical trial - randomized, placebo controlled - with 30 patients. The study uses pioglitazone at 45 mg/day for 18 months. The primary outcome measures are a battery of memory, cognition and functional instruments. Enrollment started Sept 2001.
Gabrielle Strobel
Are there any biomarkers available to measure a drug's effect on PPARg in humans?
Douglas Feinstein
To change the subject (a bit) what is the current consensus about PPAR drugs and Ab processing? Any effects?
Michael Heneka
Doug, sorry-the modem is just a bit to slow-well Magdalena Sastre and I see in AbPP stable transfectant neuroblastomas a nice suppression of Abgeneration, but only if AbPP processing has been stimulated by cytokines before. We are redoing this in PPARg knockout fibroblasts right now and the results look promising.
Gary Landreth
Doug, in a study I did with Martin Citron we saw no effect of Pioglitazone on AbPP processing in fibroblasts. Todd Golde has reported that he has looked at several PPARg agonists, none of which have regulated AbPP processing. I have talked with several pharmaceutical companies who have reproduced the Koo-Golde findings and I know of no one who has seen PPARg agonist effects.
Michael Heneka
Gary, hi, their problem is that they do these experiments in the absence of inflammation!
Gary Landreth
Michael, correct.
Elena Galea
Gary, do you think that the animal evidence is solid enough to say that PPAR regulates AbPP metabolism?
Gary Landreth
Elena, we have one nice experiment that is consistent with that conclusion in animals. Michael Heneka's lab is in the lead on looking at this angle.
June Kinoshita
Rachael, in your "AD in a dish" model, what effects of PPARg agonists do you see on AbPP processing?
Rachael Neve
June, we haven't looked -- but we definitely should! Donna, put that on the schedule!
Donna McPhie
In a limited set of samples I have not seen any effects on AbPP processing.
Rachael Neve
Oh, so you've looked -- thanks, Donna.
Gabrielle Strobel
Rachael and Donna, do you know if PPARg protects against cell cycle entry in neurons or only against apoptosis? Since PPARg was originally studied, I believe, as affecting the choice between differentiation and division in adipocytes, your findings are most intriguing.
Rachael Neve
PPARg protects against cell cycle entry as well as against apoptosis.
Donna McPhie
We have found, by examining BRDU incorporation in neurons, that PPARg blocks cell cycle entry.
Michael Heneka
Donna, we can support your data by similar findings in immunostimulated human T-lymphocytes.
Donna McPhie
Sounds good!
Douglas Feinstein
Is there any other data yet that inflammation increases secretase expression or activities?
Elena Galea
Michael, you see effects on AbPP processing after IL-1 dependent stimulation of b-site Ab cleaving enzyme (BACE). Did you test insulin degrading enzyme (IDE)?
Michael Heneka
Elena, no, however there seems to be differences regarding the secretases, depending on the cell lines we are looking at....
Gabrielle Strobel
Donna and Rachael; so PPARg would be protective for neurons? That leads you to think they might make good therapy for AD - yes?
Rachael Neve
Yes, that is correct.
Leo Kesner
A number of years ago, while studying the growth promoting properties of antibiotics, I determined that sulfonylurea oral antidiabetic drugs are excellent inhibitors of insulin degrading enzyme. I never got to test any thiazolidinediones. The action on IDE may influence the entire glucose picture.
Douglas Feinstein
Leo, that is an angle I haven't come across, i.e. TZDs blocking IDE to increase insulin-nice.
Gabrielle Strobel
Then how does IDE come in here? Given that some propose IDE degrades Ab? Do people see this as relevant? (see ARF ApoE news update)
Leo Kesner
We actually determined that the method by which bacitracin acted as a growth promoter in animals was by inhibiting IDE. A small fraction of commercial bacitracin (less than five percent does that. No, Sulfonylurea is an inhibitor of IDE.).
Douglas Feinstein
Leo, thanks... in that sense, TZDs might reduce IDE activities, thus increasing insulin (good) but reducing Abdegradation (bad).
Gabrielle Strobel
Elena and Doug, all: the field of PPARg's role in AD is very young. What are the next critical pieces of information needed to move it forward? Behavioral studies in PZD-treated transgenics? Epidemiology in humans? Other studies?
Douglas Feinstein
In the MS field, where we are finding very promising results, we have carried out surveys to identify MS patients who also have type 2 diabetes.
Rachael Neve
I think that behavioral studies in PZD-treated transgenics will yield useful information. But we also need to determine the molecular mechanism by which PPARg agonists protect!
Douglas Feinstein
We've identified about 200 such patients, of which about 50 have been taking TZDs for up to 2 years; we are now going to follow them prospectively. I think the same could be done for AD, perhaps some epidemiology (as done by Rogers) will help us here. The overall prevalence of Type 2 is about five percent.
Elena Galea
Gabrielle, in short, [we need] evidence in animal models that PPARg regulates AbPP metabolism and [leads to] functional recovery in behavioral tests. Does PPAR have any effect on LTP, for example?
Gabrielle Strobel
We are nearing the end of the hour. Please chat away as long as you like but before people start dropping out, let me thank you all very much for coming.
June Kinoshita
We have about 10 minutes left. Several possible mechanisms have been suggested regarding a role for PPARg in various model systems and in AD brain. Does anyone see a way to synthesize these findings into a bigger picture? Or do you think the various PPARg-mediated pathways are contributing independently to AD pathogenesis?
Rachael Neve
June, that's a BIG question!
Elena Galea
June, I think the latter is correct. It is a combination of antiinflammatory and metabolic effects, that we did not have the chance to talk about.
Rachael Neve
We'd like to add effects on the cell cycle to that combination, Elena.
Elena Galea
I agree, Rachael, I think the metabolic effects-regulation of mitochondrial respiration-may be linked to anti-apoptotic effects.
Rachael Neve
Thanks for the clarification, Elena; when you spoke of metabolic effects, I thought you were speaking of AbPP metabolism.
Douglas Feinstein
A remaining important "big" question is whether antiinflammatories will be good or bad for AD. In the sense that these drugs might be reducing phagocytosis.
Douglas Feinstein
The possibility exists that PPAR drugs might (!) reduce the pure 'inflammatory' effects (i.e. NO production, cytokines) while not inhibiting phagocytosis. Rachael, Donna, e.g., as soon as our paper on mitochondrial effects of TZDs in astrocytes gets accepted (!), we'll send a preprint.
Gary Landreth
Doug, there is no evidence that they affect phagocytosis. However, the TZDs have a number of effects within signaling pathways that have not been looked at extensively. The new Glaxo-Wellcome drugs will help sort this out.
Gabrielle Strobel
Gary, what are the new GW drugs?
Gary Landreth
Gabrielle, Glaxo has a number of non-TZD PPARg agonists that are high affinity, highly specific agonists.
Michael Heneka
There are 2 human post mortem studies out showing that patients taking NSAIDs have less neuronal loss, neurofibrillary tangles and activated microglia!
June Kinoshita
Michael, are those postmortem studies published?
Michael Heneka
Yes, please send me your email and I will send the details [maybe cite the paper(s) here?].
Douglas Feinstein
Gabrielle, none published.
Tilo Breidert
Doug, concerning the TZD effect in epidemiology: why can't one look retrospectively in large cohort e.g. of the Rotterdam Study (Int' Veld, > 10,000 inhabitants followed up over ten years with all the medical records) to look for AD incidence with/without TZD etc?
Douglas Feinstein
Tilo... nice project.. I'll be glad to help you!
Michael Heneka
Tilo, the drugs are not really out there for a long time.
Gary Landreth
Tilo, These drugs have only been in clinical use for a few years and the Rotterdam cohort is likely not to have sufficient exposure to see an effect yet.
Gabrielle Strobel
Tilo, I wondered about the same thing. They probably have the prescription records. That's why we invited Bruno Stricker and Monique Breteler as well, but they could not make it, unfortunately.
Douglas Feinstein
Good point, Gary.
Rachael Neve
Elena and Doug, thanks for the great write-up that you did!
Douglas Feinstein
Thanks, Rachael, hopefully we will fix it up for a journal review.
Michael Heneka
Gary, what about your stroke project, looking at stroke patients on pioglitazone or rosiglitazone?
Gary Landreth
Michael, we looked retrospectively at 200 stroke patients. The trends looked interesting but we really did not have enough patients to see any effects on incidence or severity.
Douglas Feinstein
Gabrielle, Michael, we found that 50 percent of the MS patients with diabetes have type 1...pretty unexpected.
Gary Landreth
Doug, statistically unexpected?
Douglas Feinstein
Well-powered, however.
Michael Heneka
Doug, Gary, we have some data about a PPAR polymorphism in a high percentage of MS patients.
Gary Landreth
g?
Douglas Feinstein
Could be interesting...suggests that we should all save DNA from any samples we take for later diagnostics.
Michael Heneka
Gary, lets wait another week...
Gabrielle Strobel
Have the genetics labs pursuing risk factor genes for AD looked for PPARg polymorphisms, does anyone know this?
Douglas Feinstein
I don't know about polymorphisms....
Gary Landreth
Gabrielle, no one, to my knowledge, has looked at these genes with respect to AD.
Michael Heneka
Gabrielle, we are working on that but do not have conclusive experiments.
Vitaliy Gavrilyuk
Michael, there is a PPARg polymorphism, but I do not know the details.
Michael Heneka
Vit, I think there is more than one....
Gabrielle Strobel
Thanks all for sharing all this information. I have to be off, but please continue as long as you like. Goodbye all and happy holidays.
June Kinoshita
Thank you all for being so generous, not only with your time, but also with sharing what you know with fellow participants today
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