ArticleProceedings of the National Academy of Sciences of the United States of America2021
Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 168 papers, 4 of them syntheses that pooled it.
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Who cites it
168 citing papers in PubMed, 4 syntheses or guidelines pooled it, 275 citations in OpenAlex.
- Mechanisms and Pathogenesis of Diabetic Cognitive Impairment: A Comprehensive Review.Aging and disease · 2025Pooled it
- A Systematic Review of the Effects of Capsaicin on Alzheimer's Disease.International journal of molecular sciences · 2023Pooled it
- Pooled it
- Machine Learning for Dementia Prediction: A Systematic Review and Future Research Directions.Journal of medical systems · 2023Pooled it
- CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer's disease.Alzheimer's research & therapy · 2022Trial
- Lipid Metabolism in Central Nervous System Diseases: Pathological Mechanisms and Therapeutic Advances.CNS neuroscience & therapeutics · 2026Review
- Dyslipidemia-Induced Mitochondrial Dysfunctions in the Brains Does Not Reach Pathological Levels in the ApoE-Knockout Mice.Neurochemical research · 2026Article
- Review
- Mitochondrial Dysfunction in Alzheimer's Disease and Mitochondria-Targeted Therapeutics.Cells · 2026Review
- Cholesterol metabolism in neurodegenerative diseases: mechanisms and therapeutic advances.Molecular neurodegeneration · 2026Review
- Dissecting Alzheimer's disease heterogeneity by cross-trait polygenic prediction.bioRxiv : the preprint server for biology · 2026Article
- Sequential membrane remodeling by cholesterol distinctly modulates HCN channels in naïve and neuropathic DRG neurons.The Journal of general physiology · 2026Article
- Microglial cholesterol reprogramming drives cognitive impairment under hypobaric hypoxia.Journal of neuroinflammation · 2026Article
- Article
- Age-related macular degeneration and cerebral amyloid angiopathy have similar pathologies from cholesterol-APOE-amyloid-β-complement mediated inflammation.Progress in retinal and eye research · 2026Review
- New Strategies for the Prevention and Therapy of Alzheimer's Disease Based on Stimulation of Brain Drainage and Lymphatic Clearance.International journal of molecular sciences · 2026Review
- Lipid metabolism in homeostasis and disease.Signal transduction and targeted therapy · 2026Review
- Cell-specific effects of acute sleep deprivation on transcriptomic signatures of non-neuronal cells in the mouse hippocampus and prefrontal cortex.bioRxiv : the preprint server for biology · 2026Article
- Common metabolic, environmental, and molecular mechanisms underlying neurodevelopmental and neurodegenerative disorders.Frontiers in neurology · 2026Review
- Distinct CSF lipidomic profiles are associated with five proteomic subtypes in patients with Alzheimer's disease.Molecular neurodegeneration advances · 2026Article
108 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Alzheimer's disease (AD) is characterized by the presence of amyloid β (Aβ) plaques, tau tangles, inflammation, and loss of cognitive function. Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic risk factor for sporadic AD. In vitro evidence suggests that apoE links to Aβ production through nanoscale lipid compartments (lipid clusters), but its regulation in vivo is unclear. Here, we use superresolution imaging in the mouse brain to show that apoE utilizes astrocyte-derived cholesterol to specifically traffic neuronal amyloid precursor protein (APP) in and out of lipid clusters, where it interacts with β- and γ-secretases to generate Aβ-peptide. We find that the targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid and tau burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid clusters, where it interacts with α-secretase and gives rise to soluble APP-α (sAPP-α), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on α-, β-, and γ-secretase trafficking, suggesting that the ratio of Aβ to sAPP-α is regulated by the trafficking of the substrate, not the enzymes. We conclude that cholesterol is kept low in neurons, which inhibits Aβ accumulation and enables the astrocyte regulation of Aβ accumulation by cholesterol signaling.
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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 OpenQuestion graph.