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.