PPAR-Gamma Rescue of Cognitive Function in Alzheimer's Disease

Our preliminary studies have discovered a role for a gene called PPAR-gamma in cognitive function in Alzheimer’s disease. Since virtually nothing is known about PPAR-gamma regulation in the brain, the specific aims of this project are to define the PPAR-gamma signaling axis in brain regions that underlie the types of cognitive function that PPAR-gamma agonism improves.

Recent clinical studies implicate insulin resistance as an important risk factor for Alzheimer’s disease. A very successful diabetes treatment is PPAR-gamma agonism to increase insulin sensitivity. Unfortunately, this class of drug has serious side effects to peripheral organs including the heart. We have discovered that stimulating PPAR-gamma in the brain can reverse cognitive deficits in an Alzheimer’s animal model that shows insulin resistance like humans with Alzheimer’s. This project will lead to an understanding of how brain PPAR-gamma functions in learning and memory in Alzheimer’s disease. This will lead to more selective (i.e., lacking peripheral side effects) cognitive-enhancing agents for Alzheimer’s disease patients.

Progress Updates

Overview:
Dr. Dineley’s and Dr. Denner’s team has found a number of CNS (brain) genes, gene transcripts (gene messengers), and proteins that are associated with cognitive rescue in a mouse model for Alzheimer’s disease (AD). Specifically, the team has found that many genes and proteins that are dysregulated in the CNS of AD mice are brought to normal levels with RSG treatment. The effects of RSG are specific, because these changes, for the most part, are reversed by delivering to the CNS a specific, irreversible antagonist of PPAR-gamma protein. Most importantly, the team has built a map of new protein interaction networks based upon these findings that may serve as a launching point for new models, hypotheses, and future treatments.

These endeavors have resulted in numerous abstract presentations at local, national, and international meetings, several speaking engagements, and, to date, two publications in peer-reviewed journals.

Specifics:
During the first year of the AHAF award, the team aggressively tackled the proposed studies to understand the role of PPAR-gamma in the rescue of cognitive function in Alzheimer’s disease (AD). Normally, the function of PPAR-gamma is to regulate glucose (sugar) and lipid (fat) metabolism and suppress inflammatory gene expression. In the first year, they developed the necessary tools and reagents to measure the activities of PPAR-gamma and related proteins in a mouse model of AD (called Tg2576). Tg2576 is a transgenic model of amyloid pathology, with measurable levels of amyloid protein expression, where the animals develop amyloid plaque deposits in the cortex, hippocampus, and amygdala of the brain by 10 months of age. The hippocampus of Tg2576 mice were tested, following cognitive rescue through treatment with the PPAR-gamma agonist drug, RSG.