ArticleScientific reports2025
ApoE4 requires lipidation enhancement to resolve cellular lipid and protein abnormalities following NPC1 inhibition.
Article in Scientific reports, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- APOE4 disrupts the central dogma by arresting neuronal proteome dynamics.bioRxiv : the preprint server for biology · 2026Article
- A Rapamycin Pharmacogenomic Approach for the Childhood Dementia Niemann-Pick C.Journal of inherited metabolic disease · 2026Article
- Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration.International journal of molecular sciences · 2026Review
- Article
- APOE3 astrocytes can rescue lipid abnormalities and dystrophic neurites of APOE4 human neurons.PNAS nexus · 2026Article
- Astrocytes: The Unsung Architects of Synaptic Integration and Their Role in Brain Health and Disease.Biomolecules · 2025Review
- APOE3 astrocytes can rescue lipid abnormalities and dystrophic neurites of APOE4 human neurons.bioRxiv : the preprint server for biology · 2025Article
- Human three-dimensional engineered muscle tissue characterization and intramyocellular lipid modeling.Journal of tissue engineeringArticle
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Authors and funding
6 authors.
Funding
Abstract
Apolipoprotein E (ApoE) variants are central to Alzheimer's disease (AD), Lewy body dementia (LBD) and Niemann-Pick disease type C (NPC). The ApoE4 variant elevates AD risk by 3-15-fold. ApoE's normal function in lipid transport is known. The question remains how different ApoE isoforms cause cellular pathogenesis. We determined the effects of ApoE isoforms on lipid accumulation induced by inhibiting the endo-lysosomal cholesterol transporter NPC1. In human fibroblasts and astrocytes, NPC1 inhibition caused a 4-fold cholesterol accumulation and mis-localization with altered cholesterol sensing and increased synthesis of cholesterol and triglycerides. Total APP, APP C-terminal fragments (CTF) and BACE1 levels increased 3-fold. Remarkably, the intracellular neutral lipids co-localized with APP and APP C-terminal fragments. ApoE2 and ApoE3, but not ApoE4, reduced intracellular cholesterol levels by 67% and 62%, respectively, normalized APP, BACE, CTF, and improved cell survival. ApoE4 combined with a synthetic lipopeptide, which increased the proportion of large lipidated ApoE4 particles, corrected these abnormalities. This highlights ApoE in lipid pathogenesis and targeting ApoE4 lipidation to restore ApoE4 function.
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Registered trials
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