Mechanisms of Autophagic Regulation of Aβ Metabolism Against Alzheimer’s Disease

Project Summary

The goal of our research is to understand how autophagy, a protein degradation pathway, regulates Aβ metabolism and neuronal inflammation in the brain, and to study whether autophagy-modulating compounds can be used as promising therapeutics against Alzheimer’s disease (AD). The accumulation of Aβ proteins in the brain is the major hallmark of AD. Although many therapeutic efforts have been made to target Aβ production or aggregation, no effective therapies are available so far to cure AD. We propose that AD is a degenerative condition caused by an imbalance of protein production and protein degradation, and we are very interested in testing the idea that augmenting the capacity of protein degradation reduces amyloid load, and amyloid-induced inflammation and cellular dysfunction. We thus focus on autophagy, a key “self-eating” pathway that has evolved in brain cells to get rid of damaged or toxic proteins. Impairment of autophagy has been observed during AD pathogenesis. Using new transgenic mouse model systems that show high or low autophagy levels, we are dedicated to investigating how the autophagy machinery recognizes amyloids and regulates amyloid metabolism in neurons and microglial cells in the brain, and whether pharmacologically upregulating autophagy is beneficial for restoration of cognitive functions in AD. Particularly, to specifically study the effects of autophagy in AD, we designed a drug screen for novel brain-penetrable autophagy inducers from small-molecule and natural compound libraries and identified lead compounds that can induce autophagy in the brain and restore memory in an AD mouse model. When completed, our study will reveal new mechanisms of protein degradation pathways in memory improvement, and deliver new lead compounds for the development of AD drugs.