Modulation of amyloid precursor protein cleavage by γ-secretase activating protein through phase separation
Chen Jin, Jiaoni Wang, Yumeng Wang, Bojun Jia, Xuefei Guo, Guanghui Yang, Peng Xu, Paul Greengard, Rui Zhou, Yigong Shi
Abstract
Aberrant cleavage of amyloid precursor protein (APP) by γ-secretase is closely associated with Alzheimer’s disease (AD). γ-secretase activating protein (GSAP) specifically promotes γ-secretase–mediated cleavage of APP. However, the underlying mechanism remains enigmatic. Here, we demonstrate that the 16-kDa C-terminal fragment of GSAP (GSAP-16K) undergoes phase separation in vitro and forms puncta-like condensates in cells. GSAP-16K exerts dual modulation on γ-secretase cleavage; GSAP-16K in dilute phase increases APP–C-terminal 99-residue fragment (C99) cleavage toward preferred production of β-amyloid peptide 42 (Aβ42), but GSAP-16K condensates reduce APP-C99 cleavage through substrate sequestration. Notably, the Aβ42/Aβ40 ratio is markedly elevated with increasing concentrations of GSAP-16K. GSAP-16K stably associates with APP-C99 through specific sequence elements. These findings mechanistically explain GSAP-mediated modulation of γ-secretase activity that may have ramifications on the development of potential therapeutics.