ArticleThe Journal of experimental medicine2021
GSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer's disease.
Article in The Journal of experimental medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 31 citations in OpenAlex.
- STADiffuser: high-fidelity simulation and full-view 3D modeling of spatial transcriptomics.Nature communications · 2026Article
- Alzheimer's Disease as a Multi-Layer Network Disorder: A Systems Biology Framework Integrating Multi-Omics Mechanisms.Biomedicines · 2026Review
- Gene Expression Analysis of Mitochondria-Associated Membrane (MAM)-Related Genes in ER Stress and Alzheimer's Disease.Cellular and molecular neurobiology · 2026Article
- Bioenergetics and lipid metabolism in Alzheimer's disease: From cell biology to systemic health.Journal of internal medicine · 2026Review
- Identification of novel type 1 and type 2 diabetes genes by co-localization of human islet eQTL and GWAS variants with colocRedRibbon.Cell genomics · 2025Article
- The complex web of membrane contact sites in brain aging and neurodegeneration.Cellular and molecular life sciences : CMLS · 2025Review
- Uncovering the epigenetic regulatory clues of PRRT1 in Alzheimer's disease: a strategy integrating multi-omics analysis with explainable machine learning.Alzheimer's research & therapy · 2025Article
- The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- The AICD interactome: implications in neurodevelopment and neurodegeneration.Biochemical Society transactions · 2024Review
- Modeling Lewy body disease withScience advances · 2024Article
- Causal effect of blood osteocalcin on the risk of Alzheimer's disease and the mediating role of energy metabolism.Translational psychiatry · 2024Article
- Focusing on mitochondria in the brain: from biology to therapeutics.Translational neurodegeneration · 2024Review
- Towards a Unitary Hypothesis of Alzheimer's Disease Pathogenesis.Journal of Alzheimer's disease : JAD · 2024Article
- Identification of asthma-related genes using asthmatic blood eQTLs of Korean patients.BMC medical genomics · 2023Article
- Gamma secretase activating protein promotes end-organ dysfunction after bacterial pneumonia.American journal of physiology. Lung cellular and molecular physiology · 2023Article
- To Explore the Binding Affinity of Human γ-Secretase Activating Protein (GSAP) Isoform 4 with APP-C99 Peptides.ACS omega · 2023Article
- SCAD-Brain: a public database of single cell RNA-seq data in human and mouse brains with Alzheimer's disease.Frontiers in aging neuroscience · 2023Article
- The contribution of mitochondria-associated endoplasmic reticulum membranes (MAMs) dysfunction in Alzheimer's disease and the potential countermeasure.Frontiers in neuroscience · 2023Review
- A CHCHD6-APP axis connects amyloid and mitochondrial pathology in Alzheimer's disease.Acta neuropathologica · 2022Article
- The interaction of early life factors and depression-associated loci affecting the age at onset of the depression.Translational psychiatry · 2022Article
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 3 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.