Protein Misfolding and Aggregation in the Pathogenesis of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia. In our current aging society, it is a growing public health issue. The main characteristic of AD is the accumulation of amyloid β (Aβ) plaque outside brain cells and tangled proteins made of hyperphosphorylated tau inside the cells. In AD, both Aβ and tau undergo conformational changes from their native, soluble forms into toxic oligomers and subsequently into insoluble fibrils. In this review, we explored the molecular pathways leading to protein misfolding and aggregation in AD, with a focus on the process of protein aggregation associated with disease pathogenesis and progression. First, we examine the neuronal proteostasis system, including molecular chaperones, the ubiquitin-proteasome system, and autophagy. Dysregulation of these pathways leads to the accumulation of toxic aggregates. We also discuss endoplasmic reticulum stress that activates the unfolded protein response (UPR). Persistent activation of UPR leads to inflammation, oxidative stress, and neuronal death. Additionally, we summarize important theories used to predict protein folding—Anfinsen’s dogma, energy landscape theory, nucleation–condensation, and modular folding—and discuss their effects on amyloid formation. Aβ and tau aggregation are sequence dependent; however, a prion-like mechanism moves the disease forward. These proteins also trigger mitochondrial disruption, generate reactive oxygen species, and neuroinflammation, thereby perpetuating neuronal damage. Determining the connection between misfolded proteins, cellular stress, and neuronal damage is important for creating new diagnostic tools and finding ways to slow or stop the progression of AD.