Autophagy dysfunction in Alzheimer’s disease: mechanistic insights and new therapeutic opportunities

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss due to aberrant accumulation of misfolded proteins inside and outside neurons and glial cells, leading to a loss of cellular protein homeostasis. Today, no therapy is available to block or slow down AD progression, and the mechanisms of the disease are not fully understood. Autophagy is an intracellular degradation pathway crucial to maintaining cellular homeostasis by clearing damaged organelles, pathogens, and unwanted protein aggregates. In recent years, autophagy dysfunction has gained considerable attention in AD and other neurodegenerative diseases because it has been linked to the accumulation of misfolded proteins that ultimately causes neuronal death in many of these disorders. Interestingly, autophagy-activating compounds have also shown some promising results in both clinical trials and preclinical studies. This review aims at summarizing the current knowledge on autophagy dysfunction in the context of AD pathophysiology, providing recent mechanistic insights on AD-mediated autophagic flux disruption and highlighting potential and novel therapeutic opportunities that target this system for AD therapy.