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GSAP regulates lipid homeostasis and mitochondrial function associated with 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's syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNAseq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabolism, and mitochondrial function. We demonstrated that GSAP physically interacts with the 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 that lowering GSAP expression reduces pathological effects associated with AD.

SUBMITTER: Xu P

PROVIDER: S-EPMC8222926 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description:Gamma-secretase activating protein (GSAP) plays an important role in regulating gamma-secretase activity and specificity, which contributes to the pathogenesis of Alzheimer’s disease (AD) and Down syndrome. GSAP is expressed in a variety of cell types in the bain. To elucidate the molecular function of GSAP across different cell types in the brain, we performed single nuclei RNA sequencing (sn-RNAseq) on hippocampal tissues obtained from wildtype (WT) and GSAP knockout (GKO) mice. To further investigate the pathogenic function of GSAP in the AD progression, we also determined effects of GSAP gene deletion in the J20 AD mouse model through sn-RNAseq on hippocampal tissues obtained from J20;WT and J20;GKO mice.

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

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

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