Gemfibrozil, a Lipid-Lowering Drug, Lowers Amyloid Plaque Pathology and Enhances Memory in a Mouse Model of Alzheimer's Disease via Peroxisome Proliferator-Activated Receptor α.

Abstract

Deposition of extracellular senile plaques containing amyloid-β is one of the major neuropathological characteristics of Alzheimer’s disease (AD). Therefore, targeting amyloid-β dyshomeostasis is an important therapeutic strategy for treatment of AD. In this study, we demonstrate that gemfibrozil, an FDA-approved drug for hyperlipidemia, can lower the amyloid plaque burden in the hippocampus and cortex of the 5XFAD model of AD. Additionally, gemfibrozil reduced microgliosis and astrogliosis associated with plaque in these mice. Administration of gemfibrozil also improved spatial learning and memory of the 5XFAD mice. Finally, we delineate that gemfibrozil requires the transcription factor peroxisome proliferator-activated receptor alpha (PPARα) to exhibit its amyloid lowering and memory enhancing effects in 5XFAD mice. These results highlight a new therapeutic property of gemfibrozil and suggest that this drug may be repurposed for treatment of AD.