gamma-secretase-activating protein and similar proteins
Gamma-secretase activating protein, also called GSAP or PION, selectively increases amyloid-beta production through a mechanism involving its interaction with both gamma-secretase and its substrate, the amyloid-beta precursor protein C-terminal fragment (APP-CTF). GSAP cleavage via caspase-3 is regulated and depends upon the availability of 5-lipoxygenase. Alzheimer's disease (AD), the most prevalent cause of dementia, is associated with accumulation of amyloid-beta peptide which is a major characteristic of the AD brain and responsible for some of its clinical manifestations. The anticancer drug imatinib had been shown to inhibit amyloid-beta formation without affecting Notch cleavage, by preventing GSAP interaction with the gamma-secretase substrate, APP-CTF. Thus, GSAP can serve as an amyloid-beta-lowering therapeutic target without affecting other key functions of gamma-secretase.
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