gammasecretasemediated

Gamma-secretase-mediated refers to proteolytic events governed by the gamma-secretase complex, a multi-subunit intramembrane aspartyl protease that cleaves several type I transmembrane proteins within their transmembrane domains. The complex requires four core components: presenilin (PSEN1 or PSEN2), which provides the catalytic aspartates; nicastrin; anterior pharynx-defective 1 (APH-1); and presenilin enhancer 2 (PEN-2). Gamma-secretase is active in late endosomes and the Golgi/secretory pathway and requires prior ectodomain shedding of substrates to create gamma-secretase targets.

Among its best-known substrates are Notch receptors and the amyloid precursor protein (APP). In Notch signaling, extracellular proteolysis by ADAM-family proteases releases Notch extracellular truncations that gamma-secretase then cleaves to liberate the Notch intracellular domain (NICD) that translocates to the nucleus to regulate transcription. In APP processing, beta-secretase cleavage followed by gamma-secretase yields amyloid-beta peptides and the APP intracellular domain (AICD). Gamma-secretase also processes several other substrates, including ErbB4, N-cadherin, and regulated intramembrane proteolysis of various proteins, contributing to diverse signaling outcomes.

Physiological roles include development, tissue homeostasis, and synaptic function; pathological relevance is most evident in Alzheimer's disease, where altered gamma-secretase cleavage changes Abeta generation and NICD-dependent signaling. Pharmacological strategies—gamma-secretase inhibitors and modulators—have been investigated for disease modification, but nonselective inhibition can produce adverse Notch-related toxicities. Research aims to achieve substrate-selective modulation to reduce pathogenic Abeta production while preserving essential Notch signaling.