GSAP regulates mitochondrial function through the Mitochondria-associated ER membrane in the pathogenesis of Alzheimer’s disease

Abstract

Biochemical, pathogenic and human genetic data confirm that GSAP (γ-secretase activating protein), a selective γ-secretase modulatory protein, plays important roles in Alzheimer’s disease (AD) and Down syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNA-seq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabolism, and mitochondrial function. We demonstrated that GSAP physically interacts with Fe65:APP complex to regulate APP trafficking/partitioning. GSAP is enriched in the mitochondria-associated membrane (MAM) and regulates lipid homeostasis through the amyloidogenic processing of APP. GSAP deletion generates a lipid environment unfavorable for AD pathogenesis, leading to improved mitochondrial function and the rescue of cognitive deficits in an AD mouse model. Finally, we identified a novel GSAP single-nucleotide polymorphism that regulates its brain transcript level and is associated with an increased AD risk. Together, our findings indicate that GSAP impairs mitochondrial function through its MAM localization, and lowering GSAP expression reduces pathological effects associated with AD.

Blood–Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration

“…Gamma-secretase activating protein (GSAP), which stimulates proteolysis of APP towards Aβ is enriched in mitochondria-associated membrane of the endoplasmic reticulum and interacts with APP-Fe65 complex to control APP proteolysis. It is involved in the pathogenesis of mitochondrial dysfunction and cognitive decline in Alzheimer’s disease [ 34 ]. Vice versa, mitochondrial dysfunction leads to aberrant processing of APP: inhibition of glycolysis and mitochondrial respiration as a model of metabolic stress impairs APP proteolysis and increases the probability of amyloidogenesis [ 35 ].…”