Abstract
Alzheimer’s disease (AD) is a common neurodegenerative disease whose prevalence increases with age. An increasing number of findings suggest that abnormalities in the metabolism of amyloid precursor protein (APP), a single transmembrane aspartic protein that is cleaved by β- and γ-secretases to produce β-amyloid protein (Aβ), are a major pathological feature of AD. In recent years, a large number of studies have been conducted on the APP processing pathways and the role of secretion. This paper provides a summary of the involvement of secretases in the processing of APP and the potential drug targets that could provide new directions for AD therapy.
Highlights
Alzheimer’s disease (AD) is the most common type of dementia, with approximately 60% of clinical cases of dementia being AD [1]
The etiology and pathogenesis of AD are not well understood, the polymerization and deposition of Aβ, which is produced by abnormal metabolism of Amyloid precursor protein (APP), is considered to be an important cause of AD [6]. α, β- and γ-Secretases play a crucial role in the metabolism of APP
APP-mediated a disintegrin and metalloprotease” (ADAM) mediates the hydrolysis of the Notch N-terminus, and Notch is further cleaved by γ-secretase to produce an active form of the Notch intracellular domain (NICD)
Summary
Alzheimer’s disease (AD) is the most common type of dementia, with approximately 60% of clinical cases of dementia being AD [1]. A small number of AD cases are inherited in an autosomal-dominant manner, and carriers may develop this disease after approximately 40 years of age. FAD accounts for less than 5% of the total number of AD cases and is mainly closely related to mutations in genes such as APP [7], presenilin 1 (PS1) and presenilin 2 (PS2). APP mutations change the processing of APP, leading to the production of neurotoxic Aβ42 and reduction in Aβ40. Mutations in the PS1 gene result in the deletion of the hydrophilic loop domain of the encoded protein, which leads to a change in its conformation, which in turn affects the activity of γ-secretase and increases the production of Aβ42. It was found that 12 genes are related to the course of AD, which may be used as markers for early diagnosis [9]
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