Introduction

Elena Galea and Douglas Feinstein led this live discussion on 16 December 2002. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
  

  • See the Preamble (.pdf) to this discussion
  • Look up abstracts of the Society for Neuroscience Conference in Orlando at http://sfn.scholarone.com/itin2002/index.html

    Transcript:

    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-γ (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.

     

Background

Peroxisome Proliferator Activated Receptor-γ (PPARγ) is a nuclear hormone receptor that upon activation induces de-novo gene transcription, which then leads to increased sensitivity to insulin in some cells. This has provided a rationale for the use of PPARγ agonists to treat type II diabetes. Two agonists, pioglitazone and rosiglitazone—both members of the thiazolidinedione (TZD) class of drugs—are currently approved for the treatment of diabetes. The discovery that PPARγ reduces inflammation (Combs et al., 2000; Heneka et al., 1999; Ricote et al., 1999; Combs et al., 2001; Jiang et al., 1998), together with the commercial availability of PPARγ agonists, has raised interest in TZD drugs for the treatment of neurological diseases with an inflammatory component. Studies show that TZD-PPARγ agonists are highly protective in the MPTP mouse model of Parkinson's disease (Breidert et al., 2002), and in the MOG-induced experimental allergic encephalomyelitis model of multiple sclerosis (Feinstein et al., 2002; Diab et al., 2002; Natarajan and Bright, 2002; Niino et al., 2001).

Int' Veld et al. showed in 2001 that nonsteroidal antiinflammatory drugs (NSAIDs) protect against AD. The mechanism by which they do so is now an area of active debate (see, for example, live chat). Perhaps it is less well-known in the AD community that NSAIDs can also stimulate PPARγ pathways. This raises the question of whether exerting a similar effect with different drugs, namely TZD-PPARγ could open up novel treatment strategies for AD. As with statins, TZD drugs have been taken safely for years, but unlike statins, epidemiological and mechanistic research on the relevance of TDZ drugs in AD is only now picking up steam. It is not known whether TZD-treated diabetics are at lower risk of developing AD, but there are two ongoing clinical trials investigating the effect of pioglitazone and rosiglitazone on patients with AD.

At the 32nd Annual Society for Neuroscience last month in Orlando, several presentations dealt with the effect of PPARγ in Alzheimer's. Topics included:

1. the efficacy of PPARγ agonists in patients or animal models, as compared with NSAIDs;
2. the mechanism of protection; candidates here include inhibition of inflammation, regulation of Ab production or clearance, or direct anti-poptotic effects; and
3. whether the effect of TZDs is really mediated by PPARγ or is receptor-independent.

1. Studies in animal models and humans
The notion that inflammation contributes to the development of Alzheimer's disease arose from epidemiological studies showing that long-term treatment with NSAIDs such as ibuprofen reduces the risk of developing the disease (Int't Veld et al., 2001). The observation that ibuprofen inhibits amyloid plaque burden and plaque-associated inflammation in APP-overexpressing mice provided experimental evidence that NSAIDs could reduce pathological markers associated with Alzheimer's disease (Jantzen et al., 2002; Lim et al., 2000). Eddie Koo's laboratory has shown that ibuprofen and structurally related molecules can directly reduce the production of amyloidb42 in vitro (Weggen et al., 2001). In Orlando, Morihara et al., Golde et al., and Eriksen et al. (Abstracts 722.5, 722.6, 722.7) provided in-vitro evidence indicating that the ibuprofen effect could be due to the COX-independent allosteric modification of γ-secretase. These studies support the idea that NSAIDs provide protection in Alzheimer's primarily by regulating the processing of amyloid, and that the decrease in glial inflammation is secondary to the reduction of plaque content, though this continues to be hotly debated.

Several studies sought to determine whether PPARγ activation would mimic the effect of NSAIDs. Heneka et al. reported that both pioglitazone and ibuprofen mixed into the chow of APP-overexpressing mice (London mutation) for one week decreased insoluble, i.e., plaque-associated, Ab42, but not Ab40, by 20 percent (Abstract 722.10). Glial inflammation was also reduced. Yan et al. studied the effect of pioglitazone and ibuprofen administered orally for four months in 11-month-old transgenic mice bearing the Swedish APP mutation (Abstract 483.5). Ibuprofen reduced both amyloid plaque burden and soluble amyloid Ab42 by 60 percent. By contrast, pioglitazone had no effect on plaque burden but reduced soluble Ab42 by 50 percent, and Ab40 by 20 percent. It could be argued that the drugs may independently regulate amyloid production and plaque formation—the latter being the result of deposition and removal—and that pioglitazone may primarily target production. Whether the difference in length of treatment or the mouse strain accounts for the differences between the two studies remains to be elucidated.

Feinstein et al. presented data showing that PPARγ agonists reduce the brain's inflammatory response to injection of aggregated Ab42 (Abstract 123.2). In this model, previous ablation of the locus coeruleus, a noradrenergic nucleus that is the major source of noradrenaline in brain, leads to a robust cortical inflammatory response to Ab42. Loss of locus coeruleus occurs in the majority of Alzheimer's patients, leading Feinstein to propose that reduced noradrenaline levels might exacerbate the inflammatory responses to Ab in Alzheimer's disease. Ab injection induced robust IL-1b and iNOS expression, and these responses were reduced by coinjection of ibuprofen or the TZD ciglitazone, as well as by oral pioglitazone, a more therapeutically relevant experiment.

A study by Galea et al. tested the effect of ibuprofen and pioglitazone in mice overexpressing transforming growth factor b (TGF-b (Abstract 685.11). These animals display astrocyte and microglia activation, vascular deposition of amyloid detected by thioflavin, and vascular dysfunction. Seven-week-old mice received oral ibuprofen or pioglitazone for two months. The drugs decreased the glia activation, but not the amyloid deposition. This result suggests that antiinflammatory drugs cannot interfere with TGF-induced amyloidosis, perhaps implying that they would not be appropriate for the treatment of cerebral amyloid angiopathies.

Taken together, these presentations provide evidence that orally administered PPARγ agonists can reduce brain glia inflammation. They demonstrate that some TZD drugs—at least pioglitazone—can cross the blood-brain barrier. However, while ibuprofen clearly decreases Ab42 content in APP overexpressing mice, evidence for a comparable effect of TZDs remains preliminary and conflicting, and needs to be replicated. A caveat of the studies is that they tested only one TZD dose, which was chosen based on previous studies evaluating its insulin-sensitizing effects. Hence, higher doses might be more effective on AD-related pathology. Eriksen et al. (Abstract 722.7) proposed at the meeting that higher NSAID doses may be necessary to regulate amyloid metabolism than are needed to inhibit inflammation; the same may hold for TZDs. This could create potential safety problems in future AD trials, (see related news story).

A key question regarding the use of TZDs in AD is whether they induce functional recovery, and if so, when they should be taken with respect to pathology development. TZD-treated AD mouse models have not yet been analyzed for changes in the standard learning paradigms. The available epidemiology on ibuprofen has not been yet been replicated with any of the TZD-PPARγ agonists, even though several million type II diabetes patients have been prescribed TZDs for up to five years. (Pioglitazone and rosiglitazone have been on the market since mid-1999; troglitazone was withdrawn in 1999 for liver toxicity, but patients had been taking it for three years.) This begs the question whether diabetics on TZDs are less prone to develop AD.

Despite the lack of epidemiological data and a dearth of animal studies, the safety record of the drugs has eased approval of two NIH-funded clinical trials. One is a pilot study led by Gary Landreth and David Geldmacher to examine the effects of pioglitazone on cognitive function. Patients will be treated for 18 months; results are expected in 2004. The pioglitazone dose, 45 mg./day, is the highest allowable antidiabetic dosage, so as to stay within the FDA-approved levels. The other trial, conducted by Suzanne Craft, tests the effect of rosiglitazone, and is in phase II to end in 2003. Craft et al. released some preliminary results in Orlando. People with AD appeared to have improved verbal memory after six months on rosiglitazone, thus providing a first hint for therapeutic benefit of TZD-PPARγ agonists in humans (Abstract 822.4, see related news story). The authors attribute the recovery to the insulin-sensitizing effects of rosiglitazone. In figuring out the mechanism, one must bear in mind that rosiglitazone, unlike pioglitazone, does not cross the blood-brain barrier.

2. Mechanisms of action
Could TZD-PPARγ agonists—like ibuprofen—directly regulate γ-secretase? Sagi et al. reported in-vitro data that activation of PPARs had no effect on the processing of amyloid b (Abstract 193.3). How else, then, might TZDs reduce Ab content in vivo? Sastre et al. (Abstract 483.3) showed that proinflammatory cytokines increase the production of total APP and Ab40 and 42 in neuronal cell lines N2a and SK-N-SH that transiently overexpress APP (Swedish mutation). Both ibuprofen and pioglitazone reversed this increase. Interestingly, the cytokines increased the expression and activity of BACE, but not γ-secretase. These findings indicate that inflammation and amyloid production are intertwined phenomena, the idea being that amyloid plaques or soluble Ab trigger glia activation and the release of cytokines, which, in turn, would stimulate Ab production further. Based on these findings, we speculate for the sake of discussion that TZDs could reduce the production of Ab by inhibiting the cytokine-induced expression and activation of BACE.

The findings reveal two major mechanisms by which treatment with anti-inflammatory agents could be protective in AD. One is the reduction of Ab42 production via inhibition of γ-secretase, as done by ibuprofen. For their part, TZDs and other NSAIDs might suppress the deleterious effects of inflammation, including BACE activation or the oxidative damage wrought by activated microglia. The preventive effect of ibuprofen in Alzheimer's disease could be thus due to both inflammation-dependent and independent mechanisms. By contrast, any potential therapeutic benefits of PPARγ agonists may be limited to their capacity to reduce inflammation. Note, however, one study at the meeting that showed TZDs can rescue neurons from apoptosis triggered by overexpressing FAD-APP mutations (McPhie et al., Abstract 123.1). This suggests a protective effect of TZDs independent of inflammation.

3. Is there PPARγ in brain?
While pioglitazone clearly reduces glia inflammation in vivo, the existence of PPARγ in brain remains uncertain. Wanderi et al. reported absence of expression in normal animals, and up-regulation only in neurons after ischemia (Abstract 694.13). Galea et al. did detect PPARγ expression in control mice, and down-regulation after chronic treatment with pioglitazone, but only after the antigen was concentrated by immunoprecipitation, suggesting low levels of PPARγ expression in brain (Abstract 685.11). There could be novel PPARs in brain, or TZD drugs could have PPARγ-independent effects. Richardson et al. proposed the latter in Orlando based on their finding that PPAR-antagonists failed to inhibit the antiinflammatory effect of TZDs in vitro (Abstract 304.12). Recent papers concerning the actions of PPAR agonists in diabetic models have also suggested that some TZD effects may be receptor-independent (Brunmair et al., 2001; Chawla et al., 2001; Lennon et al., 2002).

Clearly, much remains to be learned about these drugs. For this online discussion, let's focus on the two major issues of effectiveness of TZDs in AD and their mechanism(s) of action. We propose the following questions:

1. What additional animal data is needed to support the case of PPAR agonists as a treatment for AD?

2. For clinical trial planning, what are—or were—the considerations in choosing from among available TZDs? How to set the dose? NSAID trials wrestle with the problem that the dose needed to see the Ab-reducing effect exceeds what people have been taking for standard indications such as arthritis, raising safety questions. Would the doses that work in diabetes be sufficient for AD? Like ibuprofen, would TZDs work better in the prevention than in the treatment of fully developed AD?

3. What are the neuroprotective mechanisms of TZDs, and are they comparable in AD, Parkinson's disease, and multiple sclerosis? What is the contribution of inflammation-dependent and independent mechanisms?

4. Are there other, perhaps metabolic, connections between diabetes and Alzheimer's that could shed light on the potential usefulness and modus operandi of TZD drugs in both diseases?

5. Since the preferred target of NSAIDs and TZDs is Ab42, not Ab40, can these drugs do any good in cerebral amyloid angiopathies, which mostly exhibit vascular deposits of Ab40? How do we find out?

6. Are the antiinflammatory effects of ibuprofen mediated by PPARs? In APP models, is the dampening-down of glia secondary to ibuprofen's reduction of plaque deposition, or due directly to its antiinflammatory actions? In this case, is it mediated by PPARs? We believe so, since ibuprofen has been shown to have COX-independent antiinflammatory effects (Tegeder et al., 2001), and at higher doses becomes a PPARγ agonist.

7. Since activated microglia appear to carry out beneficial (phagocytosis of Ab) and deleterious actions (release of NO), is the general inhibition of microglia activation by TZDs and NSAIDs "good" or "bad"? Are there pathways exclusive to one or the other mechanism that could be exploited therapeutically? Jantzen et al. have described this year an ibuprofen analog that could specifically increase the phagocytosis of microglia.

References:
Breidert T, Callebert J, Heneka MT, Landreth G, Launay JM, Hirsch EC. Protective action of the peroxisome proliferator-activated receptor-γ agonist pioglitazone in a mouse model of Parkinson's disease. J Neurochem 2002;(82):615-624. Abstract

Brunmair B, Gras F, Neschen S, Roden M, Wagner L, Waldhausl W, Furnsinn C. Direct thiazolidinedione action on isolated rat skeletal muscle fuel handling is independent of peroxisome proliferator-activated receptor-γ-mediated changes in gene expression. Diabetes 2001;(50):2309-2315. Abstract

Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM. PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 2001;(7):48-52. Abstract

Combs CK, Bates P, Karlo JC, Landreth GE. Regulation of b-amyloid-stimulated proinflammatory responses by peroxisome proliferator-activated receptor a. Neurochem Int 2001;(39):449-457. Abstract

Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE. Inflammatory mechanisms in Alzheimer's disease: inhibition of b-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARγ agonists. J Neurosci 2000;(20):558-567. Abstract

Diab A, Deng C, Smith JD, Hussain RZ, Phanavanh B, Lovett-Racke AE, Drew PD, Racke MK. Peroxisome proliferator-activated receptor-γ agonist 15-deoxy-d (12,14)-prostaglandin J(2) ameliorates experimental autoimmune encephalomyelitis. J Immunol 2002;(168):2508-2515. Abstract

Feinstein DL, Galea E, Gavrilyuk V, Brosnan CF, Whitacre CC, Dumitrescu-Ozimek L, Landreth GE, Pershadsingh HA, Weinberg G, Heneka MT. Peroxisome proliferator-activated receptor-γ agonists prevent experimental autoimmune encephalomyelitis. Ann Neurol 2002;(51):694-702. Abstract

Heneka MT, Feinstein DL, Galea E, Gleichmann M, Wullner U, Klockgether T. Peroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase.J Neuroimmunol 1999 Dec; 22: 156-68.

Int' V, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T, Breteler MM, Stricker BH. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med 2001;(345):1515-1521. Abstract

Jantzen PT, Connor KE, DiCarlo G, Wenk GL, Wallace JL, Rojiani AM, Coppola D, Morgan D, Gordon MN. Microglial activation and b -amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal antiinflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J Neurosci 2002;(22):2246-2254. Abstract

Jiang C, Ting AT, Seed B. PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 1998;(391):82-6. Abstract

Lennon AM, Ramauge M, Dessouroux A, Pierre M. MAP kinase cascades are activated in astrocytes and preadipocytes by dPGJ2 and the thiazolidinedione ciglitazone through PPAR γ independent mechanisms involving ROS. J Biol Chem 2002. Abstract

Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, Tran T, Ubeda O, Ashe KH, Frautschy SA, Cole GM. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J Neurosci 2000;(20):5709-5714. Abstract

Natarajan C, Bright JJ. Peroxisome proliferator-activated receptor-γ agonists inhibit experimental allergic encephalomyelitis by blocking IL-12 production, IL-12 signaling and Th1 differentiation. Genes Immun 2002;(3):59-70. Abstract

Niino M, Iwabuchi K, Kikuchi S, Ato M, Morohashi T, Ogata A, Tashiro K, Onoe K. Amelioration of experimental autoimmune encephalomyelitis in C57BL/6 mice by an agonist of peroxisome proliferator-activated receptor-γ. J Neuroimmunol 2001;(116):40-8. Abstract

Ricote M, Huang JT, Welch JS, Glass CK. The peroxisome proliferator-activated receptor(PPARγ) as a regulator of monocyte/macrophage function. J Leukoc Biol 1999;(66):733-739. Abstract

Tegeder I, Pfeilschifter J, Geisslinger G. Cyclooxygenase-independent action of cyclooxygenase inhibitors. FASEB J 2001;(15):2057-2072. Abstract

Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, Findlay KA, Smith TE, Murphy MP, Bulter T, Kang DE, Marquez-Sterling N, Golde TE, Koo EH. A subset of NSAIDs lower amyloidogenic Ab42 independently of cyclooxygenase activity. Nature 2001;(414):212-216. Abstract

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  1. Alzheimer Disease and brain insulin metabolism may be assumed to be tightly coupled.

    1. Both insulin binding to its receptor and receptor autophosphorylation were found to be reduced by Ab40 and Ab42, and this effect was mediated via a decrease in the affinity of insulin binding to the a-subunit of the insulin receptor (Xie et al., 2002). This pathophysiology may be at play in cases of genetic APP abnormalities where presenilins produce increased concentrations of Ab40 and Ab42. The involvement of the a-subunit of the insulin receptor may show a link to diabetes mellitus I.

    2. Our group provided data from sporadic AD to show decreases in both brain insulin concentration and insulin receptor tyrosine kinase but an upregulation of insulin receptor density (Frölich et al., 1998). This disturbance of the b-subunit of the insulin receptor is characteristic for diabetes mellitus II. We, therefore, propose the hypothesis that sporadic AD is the brain type of diabetes mellitus II. Consequences of disturbances in insulin/insulin receptor were found in abnormalities of APP-metabolism (Gasparini et al., 2001; Solano et al., 2000), and in tau phosphorylation (Hong and Lee, 1997; Röder and Ingram, 1991). For more details see Hoyer, 2002 and Hoyer, 2002. These data provide clear evidence that, in sporadic AD, the damage in the neuronal insulin signal transduction pathway is an early disturbance, with downstream consequences in APP mismetabolism and tau hyperphosphorylation. It is, therefore, reasonable to think about therapeutic strategies to improve the function of the damaged neuronal insulin receptor (That means no vaccination, no statins!)

    3. We applied the diabetogenic compound streptozotocine into the cerebral ventricle to establish an animal model that would mimic the damage of the neuronal insulin signal transduction pathway. Long-lasting abnormalities in oxidative glucose metabolism and related metabolism similar to sporadic AD, as well as behavioral disturbances, became obvious (Nitsch and Hoyer, 1991; Lannert and Hoyer, 1988).

    4. We then studied drug effects on brain metabolism and behaviour in this animal model. Beneficial effects were found after treatment with ginkgo biloba extract (EGb 761) (Hoyer et al., 1999; Löffler et al., 2001). EGb 761 also improved dementia symptoms in patients (Le Bars et al., 1997).

    5. To influence directly the damaged function of the b-subunit of the insulin receptor, PPARg was applied in numerous cell cultures and animal models of peripheral diabetes. The data from these studies were promising. However, my intense discussions with the diabetologists of our medical faculty were disappointing in that PPARg did not show any beneficial effect in patients suffering from diabetes mellitus II based on findings of these and other diabetologists. Thus, the question remains open whether or not PPARg would help AD patients.

    6. However, never lose hope, never give up! Recent publications (Ding et al., 2002: Pender et al., 2002) showed great effects of a small-molecule insulin receptor activator on a broad spectrum of insulin signal transduction pathway-related compounds in vitro and partly in vivo, too. The effects of this compound on brain function will have to be studied. Let's start!—Siegfried Hoyer, University of Heidelberg, Germany.

    References:

    . Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease. J Neural Transm. 1998;105(4-5):423-38. PubMed.

    . Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci. 2001 Apr 15;21(8):2561-70. PubMed.

    . Insulin regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway. FASEB J. 2000 May;14(7):1015-22. PubMed.

    . Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J Biol Chem. 1997 Aug 1;272(31):19547-53. PubMed.

    . Two novel kinases phosphorylate tau and the KSP site of heavy neurofilament subunits in high stoichiometric ratios. J Neurosci. 1991 Nov;11(11):3325-43. PubMed.

    . The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: an update. J Neural Transm. 2002 Mar;109(3):341-60. PubMed.

    . The aging brain. Changes in the neuronal insulin/insulin receptor signal transduction cascade trigger late-onset sporadic Alzheimer disease (SAD). A mini-review. J Neural Transm. 2002 Jul;109(7-8):991-1002. PubMed.

    . Local action of the diabetogenic drug, streptozotocin, on glucose and energy metabolism in rat brain cortex. Neurosci Lett. 1991 Jul 22;128(2):199-202. PubMed.

    . Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci. 1998 Oct;112(5):1199-208. PubMed.

    . Damaged neuronal energy metabolism and behavior are improved by Ginkgo biloba extract (EGb 761). J Neural Transm. 1999;106(11-12):1171-88. PubMed.

    . Effect of Ginkgo biloba extract (EGb761) on glucose metabolism-related markers in streptozotocin-damaged rat brain. J Neural Transm. 2001;108(12):1457-74. PubMed.

    . A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA. 1997 Oct 22-29;278(16):1327-32. PubMed.

    . Regulation of insulin signal transduction pathway by a small-molecule insulin receptor activator. Biochem J. 2002 Oct 1;367(Pt 1):301-6. PubMed.

    . Regulation of insulin receptor function by a small molecule insulin receptor activator. J Biol Chem. 2002 Nov 15;277(46):43565-71. PubMed.

References

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  4. Anti-inflammatory Drugs Side-Step COX Cascade to Target Aβ
  5. Trials and Tribulations: Does ADAPT Have to Adapt?
  6. Orlando: Early Results Hint That Insulin-Sensitizing Drug Improves Cognition
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  1. Probing PPARγ? Agonists: Could Diabetes Drugs Treat Alzheimer's Disease?

Paper Citations

  1. . Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson's disease. J Neurochem. 2002 Aug;82(3):615-24. PubMed.
  2. . Direct thiazolidinedione action on isolated rat skeletal muscle fuel handling is independent of peroxisome proliferator-activated receptor-gamma-mediated changes in gene expression. Diabetes. 2001 Oct;50(10):2309-15. PubMed.
  3. . PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med. 2001 Jan;7(1):48-52. PubMed.
  4. . Regulation of beta-amyloid stimulated proinflammatory responses by peroxisome proliferator-activated receptor alpha. Neurochem Int. 2001 Nov-Dec;39(5-6):449-57. PubMed.
  5. . Inflammatory mechanisms in Alzheimer's disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. J Neurosci. 2000 Jan 15;20(2):558-67. PubMed.
  6. . Peroxisome proliferator-activated receptor-gamma agonist 15-deoxy-Delta(12,14)-prostaglandin J(2) ameliorates experimental autoimmune encephalomyelitis. J Immunol. 2002 Mar 1;168(5):2508-15. PubMed.
  7. . Peroxisome proliferator-activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis. Ann Neurol. 2002 Jun;51(6):694-702. PubMed.
  8. . Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med. 2001 Nov 22;345(21):1515-21. PubMed.
  9. . Microglial activation and beta -amyloid deposit reduction caused by a nitric oxide-releasing nonsteroidal anti-inflammatory drug in amyloid precursor protein plus presenilin-1 transgenic mice. J Neurosci. 2002 Mar 15;22(6):2246-54. PubMed.
  10. . PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature. 1998 Jan 1;391(6662):82-6. PubMed.
  11. . MAP kinase cascades are activated in astrocytes and preadipocytes by 15-deoxy-Delta(12-14)-prostaglandin J(2) and the thiazolidinedione ciglitazone through peroxisome proliferator activator receptor gamma-independent mechanisms involving reactive oxygenat. J Biol Chem. 2002 Aug 16;277(33):29681-5. PubMed.
  12. . Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J Neurosci. 2000 Aug 1;20(15):5709-14. PubMed.
  13. . Peroxisome proliferator-activated receptor-gamma agonists inhibit experimental allergic encephalomyelitis by blocking IL-12 production, IL-12 signaling and Th1 differentiation. Genes Immun. 2002 Apr;3(2):59-70. PubMed.
  14. . Amelioration of experimental autoimmune encephalomyelitis in C57BL/6 mice by an agonist of peroxisome proliferator-activated receptor-gamma. J Neuroimmunol. 2001 May 1;116(1):40-8. PubMed.
  15. . The peroxisome proliferator-activated receptor(PPARgamma) as a regulator of monocyte/macrophage function. J Leukoc Biol. 1999 Nov;66(5):733-9. PubMed.
  16. . Cyclooxygenase-independent actions of cyclooxygenase inhibitors. FASEB J. 2001 Oct;15(12):2057-72. PubMed.
  17. . A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 2001 Nov 8;414(6860):212-6. PubMed.
  18. . Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1997 Feb 7;272(6):3406-10. PubMed.
  19. . Peroxisome proliferator-activated receptors (PPARs) and peroxisomes in rat cortical and cerebellar astrocytes. J Neurocytol. 2001 Aug;30(8):671-83. PubMed.
  20. . Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding. Endocrinology. 2001 Oct;142(10):4195-202. PubMed.
  21. . Increased expression of cyclooxygenases and peroxisome proliferator-activated receptor-gamma in Alzheimer's disease brains. Biochem Biophys Res Commun. 1999 Jan 27;254(3):582-6. PubMed.

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