PPAR-Gamma as a Therapeutic Target in Alzheimer's Disease

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.