GSAP Regulates Amyloid Beta Production through Modulation of Amyloid Precursor Protein Trafficking

Abstract

In addition to participating in {gamma}-secretase activity, presenilin 1 (PS1) regulates trafficking and subcellular localization of {beta}-amyloid precursor protein (APP). We previously showed that gamma-secretase activating protein (GSAP) selectively modulates {gamma}-secretase activity by inducing conformational change in PS1. However, little is known whether and how GSAP might influence APP trafficking and consequent generation of {beta}-amyloid (A{beta}) peptides. Here, to explore whether GSAP has any role in regulating APP trafficking, and to systematically investigate the intracellular trafficking routes of APP, we paired total internal reflection fluorescence microscopy, high-speed line scanning microscopy, and 4D microscopy with comprehensive imaging analysis methodologies to depict the elusive modes of APP trafficking at a single-vesicle level. Mobility and diffusivity changes reveal the existence of two kinetically distinct pathways, classified into mobile and immobile pools, for vesicular APP trafficking, suggesting high association between immobile vesicle pool and amyloidogenic processing. GSAP knockdown significantly lowers immobile pool without overturning APP vesicle diffusivity, suggesting that GSAP affects vesicular APP trafficking by retaining APP in membrane microdomains known to favor amyloidogenic processing. Our study reveals a novel role of GSAP in the regulation of A{beta}-peptide formation that modulates switching of APP vesicles between immobile and mobile pools, which may help identifying new therapeutic strategies to treat Alzheimers disease.