Impaired autophagy in amyloid-beta pathology: A traditional review of recent Alzheimer's research

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. The major pathological changes in AD progression are the generation and accumulation of amyloid-beta (Aβ) peptides as well as the presence of abnormally hyperphosphorylated tau proteins in the brain. Autophagy is a conserved degradation pathway that eliminates abnormal protein aggregates and damaged organelles. Previous studies have suggested that autophagy plays a key role in the production and clearance of Aβ peptides to maintain a steady-state of Aβ peptides levels. However, a growing body of evidence suggests that autophagy is significantly impaired in the pathogenesis of AD, especially in Aβ metabolism. Therefore, this article reviews the latest studies concerning the mechanisms of autophagy, the metabolism of Aβ peptides, and the defective autophagy in the production and clearance of Aβ peptides. Here, we also summarize the established and new strategies for targeting autophagy in vivo and through clinical AD trials to identify gaps in our knowledge and to generate further questions.

Numerical and analytical simulation of the growth of amyloid-β plaques

“…5a). However, if Aβ aggregates are degraded (e.g., by autophagy [54]), the cessation of monomer supply results in the reduction ( μm, the plaque's diameter after 20 years of growth is approximately 50 μm, which agrees with the representative diameter of an Aβ plaque observed in [32]. In the case of infinite half-life for Aβ monomers, the approximate solution provided by Eq.…”

“…5a). However, if Aβ aggregates are degraded (e.g., by autophagy [54]), the cessation of monomer supply results in the reduction ( T 1/ 2, B = 10 4 × 2.31×10 4 s) or complete disappearance ( T 1/ 2, B = 2.31×10 4 s and T 1/ 2, B = 10 2 × 2.31×10 4 s) of the Aβ plaques (Fig. 5b).…”

The contribution of mitochondria-associated endoplasmic reticulum membranes (MAMs) dysfunction in Alzheimer’s disease and the potential countermeasure

“…Autophagy plays a vital role in the generation and clearance of Aβ. Abnormal autophagy is involved in the development of AD ( Yuan et al, 2022 ). Activation of autophagy alleviates pathological characters and cognitive deficits in APP/PS1 mice ( Yang et al, 2023 ).…”