GSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer's disease.

TitleGSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2021
AuthorsXu P, Chang JC, Zhou X, Wang W, Bamkole M, Wong E, Bettayeb K, Jiang L-L, Huang T, Luo W, Xu H, Nairn AC, Flajolet M, Ip NY, Li Y-M, Greengard P
JournalJ Exp Med
Date Published2021 08 02
KeywordsAging, Alzheimer Disease, Amyloid beta-Protein Precursor, Animals, Base Sequence, Disease Models, Animal, Hippocampus, Homeostasis, Humans, Lipid Metabolism, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Mitochondrial Membranes, Models, Biological, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Open Field Test, Phosphorylation, Protein Binding, Protein Transport, Proteins, Transcription, Genetic

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.

Alternate JournalJ Exp Med
PubMed ID34156424
PubMed Central IDPMC8222926
Grant ListP50 AG047270 / AG / NIA NIH HHS / United States
P30 DA018343 / DA / NIDA NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 AG061350 / AG / NIA NIH HHS / United States
P30 AG066508 / AG / NIA NIH HHS / United States
R01 AG062306 / AG / NIA NIH HHS / United States