Gammasecretase

Gamma-secretase is a multi-subunit intramembrane protease that cleaves transmembrane proteins within their membrane-spanning region. The active complex is composed of presenilin 1 or 2 (PSEN1 or PSEN2), which provides the catalytic aspartate residues, along with the auxiliary components nicastrin, anterior pharynx-1 (APH-1), and presenilin enhancer 2 (PEN-2). Presenilin undergoes endoproteolysis to generate N-terminal and C-terminal fragments that assemble into the mature, active site of the enzyme.

The best-known substrates of gamma-secretase are Notch receptors and the amyloid precursor protein (APP). Gamma-secretase performs the S3 intramembrane cleavage after ectodomain shedding, releasing the Notch intracellular domain (NICD) that enters the nucleus to regulate gene expression and enabling Notch signaling. In the case of APP, gamma-secretase generates amyloid-beta peptides, including Aβ40 and the aggregation-prone Aβ42, which are central to amyloid pathology in Alzheimer’s disease.

Biological significance and disease relevance are linked to its role in development and neural function. Gamma-secretase activity is essential for normal development, and genetic mutations in PSEN1 or PSEN2 can alter enzyme activity or substrate specificity, contributing to early-onset familial Alzheimer’s disease. Dysregulated APP processing and amyloid-beta accumulation are key features of Alzheimer’s pathology, while Notch signaling disruption can produce adverse effects.

Therapeutically, gamma-secretase inhibitors (GSIs) and gamma-secretase modulators (GSMs) have been explored for Alzheimer’s disease. GSIs broadly suppress substrate processing and have caused unacceptable adverse effects due to Notch inhibition, limiting their clinical use. GSMs aim to modify APP processing with fewer Notch-related side effects. Semagacestat is a notable example of a GSI that failed in trials due to safety concerns.