ArticleProgress in neurobiology2021
ApoE4 activates C/EBPβ/δ-secretase with 27-hydroxycholesterol, driving the pathogenesis of Alzheimer's disease.
Article in Progress in neurobiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 2 of them syntheses that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 2 syntheses or guidelines pooled it, 44 citations in OpenAlex.
- C/EBPβ: A transcription factor associated with the irreversible progression of Alzheimer's disease.CNS neuroscience & therapeutics · 2024Pooled it
- Confirmed Synergy Between the ɛ4 Allele of Apolipoprotein E and the Variant K of Butyrylcholinesterase as a Risk Factor for Alzheimer's Disease: A Systematic Review and Meta-Analysis.Journal of Alzheimer's disease reports · 2023Pooled it
- Dyslipidemia-Induced Mitochondrial Dysfunctions in the Brains Does Not Reach Pathological Levels in the ApoE-Knockout Mice.Neurochemical research · 2026Article
- The Use of Statins in Parkinson's and Alzheimer's Disease: A 2021-2025 State-of-the-Art Review of Clinical and Preclinical Evidence.Pharmacology research & perspectives · 2026Review
- Lipid metabolism, neuroinflammation, and oxidative stress in Alzheimer disease: an integrated mechanistic review.Acta neurologica Belgica · 2026Review
- Organelle stress in NLRP3 inflammasome: a central mediator of neurodegenerative diseases.Molecular neurodegeneration · 2026Review
- Why 11β-HSD1 inhibitors show variable efficacy in Alzheimer's therapy: an APOE4-dependent HSD11B1 mechanism.Theranostics · 2026Article
- 27-Hydroxycholesterol triggers microglial senescence subsequent to iron over-loading contributes to brain aging, suppressed by Deferoxamine.npj aging · 2025Article
- Mechanisms of high-density lipoprotein in regulating blood-brain barrier function: insights and implications.Fluids and barriers of the CNS · 2025Review
- The multifaceted roles of apolipoprotein E4 in Alzheimer's disease pathology and potential therapeutic strategies.Cell death discovery · 2025Review
- PGRN as an emerging regulator of lipid metabolism in neurodegenerative diseases.Communications biology · 2025Review
- Visualize neuronal membrane cholesterol with split-fluorescent protein tagged YDQA sensor.Journal of lipid research · 2025Article
- Oxymatrine impedes Alzheimer's progression via the attenuation of hypercholesterolemia and fibrosis.Metabolic brain disease · 2025Article
- Maternal behavior promotes resilience to adolescent stress in mice through a microglia-neuron axis.Nature communications · 2025Article
- ApoE3 R136S binds to Tau and blocks its propagation, suppressing neurodegeneration in mice with Alzheimer's disease.Neuron · 2025Article
- N-terminomics profiling of naïve and inflamed murine colon reveals proteolytic signatures of legumain.Journal of cellular physiology · 2025Article
- Brain derived β-interferon is a potential player in Alzheimer's disease pathogenesis and cognitive impairment.Alzheimer's research & therapy · 2024Article
- Thy1-ApoE4/C/EBPβ double transgenic mice act as a sporadic model with Alzheimer's disease.Molecular psychiatry · 2024Article
- Plasma oxysterols are associated with serum lipids and dementia risk in older women.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer's disease in mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
ApoE4, an apolipoprotein implicated in cholesterol transport and amyloid-β (Aβ) metabolism, is a major genetic risk determinant for Alzheimer's Disease (AD) and drives its pathogenesis via Aβ-dependent and -independent pathways. C/EBPβ, a proinflammatory cytokines-activated transcription factor, is upregulated in AD and mediates cytokines and δ-secretase expression. However, how ApoE4 contributes to AD pathogenesis remains incompletely understood. Here we show that ApoE4 and 27-hydroxycholesterol (27-OHC) co-activate C/EBPβ/δ-secretase signaling in neurons, mediating AD pathogenesis, and this effect is dependent on neuronal secreted Aβ and inflammatory cytokines. Inhibition of cholesterol metabolism with lovastatin diminishes neuronal ApoE4's stimulatory effects. Furthermore, ApoE4 and 27-OHC also mediate lysosomal δ-secretase leakage, activation, secretion and endocytosis. Notably, 27-OHC strongly activates C/EBPβ/δ-secretase pathway in human ApoE4-TR mice and triggers AD pathologies and cognitive deficits, which is blocked by C/EBPβ depletion. Hence, our findings demonstrate that ApoE4 and 27-OHC additively trigger AD pathogenesis via activating C/EBPβ/δ-secretase pathway. Lowering cholesterol levels with statins should benefit the ApoE4 AD carriers.
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Registered trials
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