γ-Secretase in the pathogenesis of Alzheimer’s disease and therapeutic potential of its modulators

Abstract

Alzheimer’s disease is caused by the loss of synaptic connections and neurons in the brain. One of the characteristic morphological features of Alzheimer’s disease is the formation of amyloid plaques containing β-amyloid peptide. The β-amyloid peptide is produced from the amyloid precursor protein (APP) through sequential proteolytic cleavages by α-secretase, β-secretase, and γ-secretase, resulting in β-amyloid peptide clustering into amyloid plaques, a key pathogenic event in Alzheimer’s disease. Since γ-secretase mediates the final cleavage that releases β-amyloid peptide, it has been widely studied as a potential drug target for the treatment of Alzheimer’s disease. γ-Secretase is a transmembrane protein complex consisting of four subunits: presenilin, nicastrin, Aph-1, and Pen-2, which are necessary for its function. γ-Secretase has been shown to cleave more than 140 substrates, including the APP and Notch. Clinical trials of γ-secretase inhibitors for Alzheimer’s disease have shown side effects due to inhibition of Notch signaling. It has been concluded that alternative compounds with more specific regulation or modulation of γ-secretase are needed. A number of γ-secretase modulators have now been developed. To modulate γ-secretase and better understand its complex biology, research focuses on identifying inhibitor and modulator binding sites within γ-secretase’s structure, as well as intermediate binding proteins that modulate γ-secretase. This article discusses recent advances over the past decade in studying the role of γ-secretase in the treatment of Alzheimer’s disease.