PPAR-gamma as a Therapeutic Target in Alzheimer's Disease
Detailed Non-Technical Summary
Alzheimer's disease is characterized by the deposition of b amyloid (Ab) within the brain and there is good biological evidence that that therapies that reduce Ab deposition and enhance its clearance from the brain will be beneficial. This application investigates the ability of a new class of drug that activate a transcription factor, termed peroxisome proliferator-activated receptor gamma (PPARg). Importantly, drugs that activate PPARg are already in clinical use and have been shown to result in enhanced learning and memory in AD patients. The central problem is that we do not know how the drugs work to elicit the behavioral improvement and this application is focused on establishing the mechanism of drug action. We show that treatment of animal models of AD with PPARg stimulators lead to lower levels of plaque deposition. Moreover, we show that this is likely due to the ability of the drug to stimulate Ab degradation, reducing brain levels of amyloid. We think that PPARg activation works to stimulate the production of factors that allow cellular proteases to cut the amyloid peptides into pieces too small to be deposited. This research provides an explanation for why the present generation of drug that PPARg are beneficial and will inform the development of the next generation of drugs that target this receptor.
Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL, Richardson JC, Smith JD, Comery TA, Riddell D, Holtzman DM, Tontonoz P, Landreth GE. ApoE promotes the proteolytic degradation of Abeta. Neuron. 2008 Jun 12;58(5):681-93.
Jiang, Q., Heneka, M., and Landreth, G.E. (2008) The Role of Peroxisome Proliferator-Activated Receptor-gamma (PPARgamma) in Alzheimer's Disease. CNS Drugs 22(1): 1-14.
Heneka, M., and Landreth G.E. (2007) PPARs in the brain. Biochimica et Biophysica Acta 1031-1045.
Heneka, M.T., Landreth, G.E., and Hull, M. (2007) Drug Insight: effects of mediated by peroxisome proliferator-activated receptor-? in CNS disorders. Nature Vol. 3 No. 9.
Mandrekar S, Jiang Q, Lee CY, Koenigsknecht-Talboo J, Holtzman DM, Landreth GE. Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. J. Neurosci. 29:4252-4262, 2009.