Gamma-secretase activating protein (GSAP)

Gamma-secretase activating protein (GSAP) is a modulatory protein encoded by the PION gene in humans[4]. Its principal biologically active form is a 16 kDa C-terminal fragment (GSAP-16K), which specifically enhances gamma-secretase–mediated cleavage of amyloid precursor protein (APP), thereby increasing production of beta-amyloid peptides, especially Aβ42, a key factor in Alzheimer's disease[1][4]. GSAP exerts its function by binding both gamma-secretase and the APP substrate, increasing their affinity and selectivity[4]. Although not an essential subunit of the gamma-secretase complex, GSAP and other gamma-secretase modulatory proteins fine-tune enzymatic activity, impacting neurodegeneration and potentially cancer[2]. Imatinib has been shown to interact with GSAP and modulate gamma-secretase activity[2][5]. Excessive GSAP function enhances Aβ42/Aβ40 ratio, underscoring its disease relevance and therapeutic potential—though targeting GSAP or its interaction with gamma-secretase requires caution due to possible side effects from imprecise modulation of this enzyme[1][5].

Other names

Protein pigeon homologPIONGSAP-16KGamma-secretase-activating protein 16 kDa C-terminal formLOC54103

Allosteric modulation of gamma-secretase activity, leading to increased APP cleavage and beta-amyloid (Aβ) production