ALZHEIMER DISEASE (AD) MECHANISMS AND INTERVENTIONS: INSIGHTS FROM TRANSGENIC CAENORHABDITIS ELEGANS MODEL

Abstract

Alzheimer disease is characterized by the formation of amyloid beta (Ab) plaque and neurofibrillary tangles in the brain. Here, I have investigated the mechanisms underlying Ab-mediated toxicity in a novel transgenic Caenorhabditis elegans strain with pan-neuronal human Ab expression, GRU102. I found metabolic alterations and oxidative stress as early events that precede global protein aggregation in the GRU102 animals. Treatment with Metformin rescued lifespan detriment of those transgenic animals by restoring metabolic health. Remarkably, Metformin treatment also normalizes levels of protein aggregates in the transgenic animals, suggesting protein aggregation as a secondary event induced by metabolic dysfunction in AD. Using the GRU102 strain, I developed a potentially high-throughput screening platform and identified Lithium as a positive hit through my preliminary drug screen. I further found synergistic effects of Lithium and Metformin combinatorial treatment in improving healthspan of the GRU102 animals, suggesting the potential of combinatorial treatment for AD therapy.