The emerging roles of protein homeostasis-governing pathways in Alzheimer's disease

Abstract

Pathways governing protein homeostasis are involved in maintaining the structural, quantitative, and functional stability of intracellular proteins and involve the ubiquitin-proteasome system, autophagy, endoplasmic reticulum, and mTOR pathway. Due to the broad physiological implications of protein homeostasis pathways, dysregulation of proteostasis is often involved in the development of multiple pathological conditions, including Alzheimer's disease (AD). Similar to other neurodegenerative diseases that feature pathogenic accumulation of misfolded proteins, Alzheimer's disease is characterized by two pathological hallmarks, amyloid-β (Aβ) plaques and tau aggregates. Knockout or transgenic overexpression of various proteostatic components in mice results in AD-like phenotypes. While both Aβ plaques and tau aggregates could in turn enhance the dysfunction of these proteostatic pathways, eventually leading to apoptotic or necrotic neuronal death and pathogenesis of Alzheimer's disease. Therefore, targeting the components of proteostasis pathways may be a promising therapeutic strategy against Alzheimer's disease.

Figure 1

A schematic illustration of protein‐governing pathways in mammalian cells

Figure 2

Mechanistic correlations between ubiquitin–proteasome system and Alzheimer's disease. N8: NEDD8; UB: ubiquitin

Figure 3

Pathological associations between mammalian autophagy machinery and Alzheimer's disease

Figure 4

Core interactions between the mTOR pathway and Alzheimer's disease

Figure 5

Pathological linkage between UPR and Alzheimer's disease