Presenilin 1-containing γ-secretase complex (PS1-γ-secretase)

The Presenilin 1-containing γ-secretase complex is a multi-subunit intramembrane-cleaving aspartyl protease essential for the processing of various Type I transmembrane proteins (PubMed: 25524711). It consists of four core subunits: Presenilin 1 (the catalytic component), Nicastrin, Anterior pharynx-defective 1 (APH-1), and Presenilin enhancer 2 (PEN-2) (PubMed: 21526838). The complex plays a pivotal role in the pathogenesis of Alzheimer's disease by cleaving the amyloid precursor protein (APP) to generate amyloid-beta (Aβ) peptides, particularly the neurotoxic Aβ42 isoform (AlzForum). Mutations in the PSEN1 gene are the most common cause of early-onset familial Alzheimer's disease, often leading to an increased Aβ42/Aβ40 ratio (StatPearls: NBK549856). Beyond APP, the complex is critical for Notch signaling, which regulates cell fate and differentiation; dysregulation of this pathway is implicated in various cancers (PubMed: 21528937). Therapeutic strategies have focused on gamma-secretase inhibitors (GSIs) and gamma-secretase modulators (GSMs). While GSIs block all proteolytic activity, they often cause significant side effects due to the inhibition of Notch signaling, leading to the development of GSMs that specifically target APP processing without affecting Notch (PubMed: 21526838).

Other names

Gamma-secretase complexPS1-GSCPresenilin-1 complexPSEN1-containing gamma-secretasePS1-gamma-secretase

Inhibition or modulation of the intramembrane proteolytic activity of the complex, specifically targeting the catalytic subunit Presenilin 1 to reduce the production of amyloid-beta 42 or inhibit Notch signaling.