Development of Mitophagy-inducing Small Molecules as Therapeutics for Aging and Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the leading cause of dementia in those over the age of65. The underlying molecular basis for the disease remains elusive. Rather than simply viewing individual diseases in isolation, researchers have turned to studying the contribution of common age-related processes. One such process is loss in mitochondrial function, normally maintained by defective mitochondrial clearance via mitophagy. Mitophagy slows with age and with various age-related conditions including AD. An agent which has received considerable attention is urolithin A (UA) which has recently been reported to elicit neuroprotection in a variety of AD models. As part of an independent small molecule screen, we identified a second structurally-related compound we named ‘mitophagy inducing compound’ (MIC). Using C. elegans as an initial validation tool, we showed that both compounds significantly improve mitochondrial function, protect against neuronal cell loss, and extend lifespan. These effects were translatable to both in vitro and in vivo mammalian models. To identify potential drug targets, we performed Cellular Thermal Shift Assay (CETSA). Preliminary data from knockdown of identified targets suggest the involvement of a mito-hormetic mechanism which acts to restore overall mitochondrial health. These studies may have important implications for how these compounds elicit their effects.