Gamma-secretase subunit APH-1 (APH-1)

Gamma-secretase subunit APH-1 is an essential component of the gamma-secretase complex, a four-subunit intramembrane aspartyl protease [UniProt Q96BI3]. It serves as a stabilizing scaffold during the assembly of the complex, which also includes presenilin, nicastrin, and presenilin enhancer 2 (PEN-2) [Francis et al., 2002; PubMed: 12297050]. The primary biological role of the complex is the intramembrane proteolysis of over 100 substrates, including the amyloid precursor protein (APP) and the Notch receptor [De Strooper, 2003; PubMed: 12671654]. In Alzheimer's disease, the cleavage of APP by gamma-secretase produces neurotoxic amyloid-beta (Aβ) peptides, which aggregate into plaques [Selkoe and Hardy, 2016; PubMed: 27029318]. Consequently, APH-1 and the wider complex have been major targets for drug development, leading to the creation of gamma-secretase inhibitors (GSIs) and modulators (GSMs) [Wolfe, 2012; PubMed: 22473134]. While GSIs like semagacestat failed in clinical trials for Alzheimer's due to off-target effects related to Notch inhibition, newer agents like nirogacestat are being utilized for Notch-dependent conditions such as desmoid tumors [FDA, 2023].

Other names

Anterior pharynx-defective 1APH1APH-1AAPH-1BGamma-secretase subunit APH-1AGamma-secretase subunit APH-1B

Gamma-secretase inhibition and modulation