{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Gamma‐secretase activating protein (GSAP) is a pivotal modulator of γ‐secretase that selectively enhances the amyloidogenic processing of the amyloid precursor protein (APP) to produce neurotoxic β‐amyloid (Aβ) peptides implicated in Alzheimer’s disease (AD). GSAP functions by binding both the γ‐secretase complex and the APP C‐terminal fragment (APP‐CTF or C99), thereby driving the enzyme’s specificity toward APP cleavage while sparing essential substrates such as Notch."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " Moreover, GSAP is proteolytically processed to yield an active 16‐kDa fragment whose unique biophysical properties—including phase separation and substrate sequestration—further influence the Aβ42/Aβ40 ratio and, consequently, amyloid plaque formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Genetic and epigenetic studies have linked increased GSAP expression and specific single-nucleotide polymorphisms, as well as its regulation by microRNAs (notably miR-4422), to an elevated AD risk."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": " In addition, inflammatory pathways—for instance, those involving 5-lipoxygenase that activate caspase-3—regulate GSAP formation and link neuroinflammation to enhanced amyloidogenic processing."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Mechanistic studies indicate that GSAP induces conformational rearrangements within the γ‐secretase complex, specifically affecting the spatial orientation of presenilin subunits, to promote APP cleavage without perturbing the processing of other substrates."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Collectively, these findings establish GSAP as a key factor in directing γ‐secretase specificity and underscore its promise as a therapeutic target for reducing pathogenic Aβ production in AD.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Gen He, Wenjie Luo, Peng Li, et al. 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