γ-secretase targeting in Alzheimer's disease

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders and is characterized by memory loss and cognitive decline. The amyloid cascade hypothesis posits that the pathogenesis of AD is initiated by the oligomerization and accumulation of toxic amyloid-β (Aβ) peptides within the brain. The aspartic protease γ-secretase, which catalyzes the final step in the cellular production of Aβ peptides, has been identified as a potential target for anti-amyloid intervention strategies. This target has attracted increasing attention in recent years, and novel small molecules have been developed as selective γ-secretase inhibitors and γ-secretase modulators. This review aims to discuss the role of γ-secretase protein hydrolysis activity in the pathogenesis of AD and to review the molecular mechanisms and prospects for the future development of strategies that target γ-secretase to intervene in AD development, which is expected to provide new ideas for the treatment of AD.