New Insights Into Autophagy Dysfunction Related to Amyloid Beta Toxicity and Neuropathology in Alzheimer's Disease

Abstract

The fine control of neuronal proteostasis is an essential element that preserves cell viability. Advancing age is a major risk factor for Alzheimer's disease (AD), and autophagy is thought to dictate normal and pathological aging through intricate molecular machinery controlling protein aggregation. Although the role of autophagy dysfunction in AD is known, the dynamic changes during the progression of the disease remain unclear. Recent studies have provided new insight into the molecular mechanisms that link defective autophagy and cellular fate, underscoring the pathogenic events associated with AD. Here, we will focus on recent studies that underpin a distinct role for autophagy deficits and highly localized autophagic defects, impacting primarily the amyloidogenic pathway activity. By uniquely assessing the dynamic changes in key proteins during the disease progression in the context of the autophagy machinery function and amyloid beta toxicity, specifically, a connect between protein degradation failure and cell death susceptibility is revealed which may suggest new avenues for the development of better targeted therapeutic interventions.

Keywords: Alzheimer's disease; Amyloid; Apoptosis; Autophagosome; Autophagy; Endosome; Lysosome.