ArticleNeuron2023
Neuronal γ-secretase regulates lipid metabolism, linking cholesterol to synaptic dysfunction in Alzheimer's disease.
Article in Neuron, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 49 citations in OpenAlex.
- Targeting innovative therapeutic approaches to the hallmarks of aging to combat Alzheimer's disease.Neural regeneration research · 2026Article
- Presynaptic accumulation of APP-CTFβ may contribute to synaptic dysfunction in Alzheimer's disease.The EMBO journal · 2026Article
- Deep Plasma Proteomics-Based Diagnostic Panel for Early Detection of Amnestic Mild Cognitive Impairment.Journal of proteome research · 2026Article
- Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration.International journal of molecular sciences · 2026Review
- Cholesterol metabolism in neurodegenerative diseases: mechanisms and therapeutic advances.Molecular neurodegeneration · 2026Review
- SGK1 inhibition restores excitability of cortical neurons derived from Alzheimer's disease patients.Neurobiology of disease · 2026Article
- Dnmt1 mediates epigenetic restriction of invasive traits in clonal crayfish.Nature communications · 2026Article
- Amyloid-β and Mitochondrial Membranes: A Missing Link in Alzheimer's Pathogenesis.Molecular neurobiology · 2026Review
- APOE3 astrocytes can rescue lipid abnormalities and dystrophic neurites of APOE4 human neurons.PNAS nexus · 2026Article
- Plasma lipidomic fingerprinting enables high-accuracy biomarker discovery for Alzheimer's disease: a targeted LC-MRM/MS approach.GeroScience · 2026Article
- Exercise-conditioned extracellular vesicles in Alzheimer's disease: a multi-organ signaling network linking peripheral adaptation to brain pathology.Frontiers in immunology · 2026Review
- Review
- APOE3 astrocytes can rescue lipid abnormalities and dystrophic neurites of APOE4 human neurons.bioRxiv : the preprint server for biology · 2025Article
- Targeting the awry Aβ pathway in Alzheimer's disease: hype and hurdles.Inflammopharmacology · 2025Review
- Impact Induces Phagocytic Defect in Reactive Microglia.bioRxiv : the preprint server for biology · 2025Article
- Pen-2 regulates glial homeostasis by coordinating self-renewal and transdifferentiation programs in oligodendrocyte precursor cells.Stem cell reports · 2025Article
- Astrocyte Lipid Droplet Dynamics Orchestrate Neurological Disorders and Therapeutic Horizons.Small science · 2025Review
- Dishevelled localization and function are differentially regulated by structurally distinct sterols.iScience · 2025Article
- PBX3-HMGCR Axis Promotes Hepatocellular Carcinoma Progression Through Enhancing De Novo Cholesterol Biosynthesis.International journal of molecular sciences · 2025Article
- The role of lipid metabolism in cognitive impairment.Arquivos de neuro-psiquiatria · 2025Review
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
Presenilin mutations that alter γ-secretase activity cause familial Alzheimer's disease (AD), whereas ApoE4, an apolipoprotein for cholesterol transport, predisposes to sporadic AD. Both sporadic and familial AD feature synaptic dysfunction. Whether γ-secretase is involved in cholesterol metabolism and whether such involvement impacts synaptic function remains unknown. Here, we show that in human neurons, chronic pharmacological or genetic suppression of γ-secretase increases synapse numbers but decreases synaptic transmission by lowering the presynaptic release probability without altering dendritic or axonal arborizations. In search of a mechanism underlying these synaptic impairments, we discovered that chronic γ-secretase suppression robustly decreases cholesterol levels in neurons but not in glia, which in turn stimulates neuron-specific cholesterol-synthesis gene expression. Suppression of cholesterol levels by HMG-CoA reductase inhibitors (statins) impaired synaptic function similar to γ-secretase inhibition. Thus, γ-secretase enables synaptic function by maintaining cholesterol levels, whereas the chronic suppression of γ-secretase impairs synapses by lowering cholesterol levels.
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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 OpenQuestion graph.