Exploring autophagy as a target for Alzheimer's Disease

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Project Abstract Alzheimer’s disease (AD) is a degenerative brain disease that affects more than 5 million Americans and is the 6th leading cause of death in the United States. There are no known drugs that slow its progression and given its increasing prevalence, the development of new therapeutic options represents an enormous unmet clinical need. The discovery of new therapeutic targets and new drugs that can prevent the neurodegeneration and buildup of neurotoxic protein aggregates, which are the hallmark of AD, are desperately needed. One emerging pathway that has recently garnered attention is autophagy, a highly conserved catabolic pathway that is responsible for the degradation and recycling of cellular components ranging from proteins to whole organelles. There is emerging evidence that autophagic dysfunction is involved in the pathogenesis of AD. Indeed, buildup of autophagic vesicular structures in neurons is also a hallmark in the progression of the disease. It is thought that autophagy is responsible for clearing misfolded protein aggregates, and when it is dysfunctional or can no longer clear the aggregates efficiently enough, neurotoxicity can occur. However, no good drugs exist that increase autophagy to test this hypothesis and serve as potential new drugs. We are proposing to develop small molecules to selectively increase the autophagic rate as a novel therapeutic strategy for slowing the progression of AD. Because protein aggregation is the key phenomenon at the center of AD, we believe that activating the pathway that clears large protein aggregates could provide a novel therapeutic strategy for this disease.