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CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer’s disease
Abstract
Abnormalities in neuronal cholesterol homeostasis have been suspected or observed in several neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. However, it has not been demonstrated whether an increased abundance of cholesterol in neurons in vivo contributes to neurodegeneration. To address this issue, we used RNA interference methodology to inhibit the expression of cholesterol 24-hydroxylase, encoded by the Cyp46a1 gene, in the hippocampus of normal mice. Cholesterol 24-hydroxylase controls cholesterol efflux from the brain and thereby plays a major role in regulating brain cholesterol homeostasis. We used an adeno-associated virus vector encoding short hairpin RNA directed against the mouse Cyp46a1 mRNA to decrease the expression of the Cyp46a1 gene in hippocampal neurons of normal mice. This increased the cholesterol concentration in neurons, followed by cognitive deficits and hippocampal atrophy due to apoptotic neuronal death. Prior to neuronal death, the recruitment of the amyloid protein precursor to lipid rafts was enhanced leading to the production of β-C-terminal fragment and amyloid-β peptides. Abnormal phosphorylation of tau and endoplasmic reticulum stress were also observed. In the APP23 mouse model of Alzheimer’s disease, the abundance of amyloid-β peptides increased following inhibition of Cyp46a1 expression, and neuronal death was more widespread than in normal mice. Altogether, these results suggest that increased amounts of neuronal cholesterol within the brain may contribute to inducing and/or aggravating Alzheimer’s disease. Abnormalities in brain cholesterol homeostasis are suspected in several neurodegenerative disorders. Using RNA interference in mice, Djelti et al. inhibit the expression of Cyp46a1, which encodes an enzyme that controls brain cholesterol efflux. Increased cholesterol in hippocampal neurons induces apoptosis and triggers the production of Aß peptides and phosphorylated tau.
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“Regulation of pTau by CYP46A1 is also conserved in adult (mice) brains where genetic inhibition of CYP46A1 enhances abnormal phosphorylation of Tau (Djelti et al., 2015), and overexpression of CYP46A1 in transgenic Tau mice rescues cognitive decline (Burlot et al., 2015).”
From Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer’s Disease Neurons (2019) · cites this paper as Djelti et al., 2015
In the citing paper
“Regulation of pTau by CYP46A1 is also conserved in adult (mice) brains where genetic inhibition of CYP46A1 enhances abnormal phosphorylation of Tau (Djelti et al., 2015), and overexpression of CYP46A1 in transgenic Tau mice rescues cognitive decline (Burlot et al., 2015).”
From Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer’s Disease Neurons (2019) · cites this paper as Djelti et al., 2015
In the citing paper
“In addition, the presence of high-risk alleles in both CYP17 and CYP19 increased the risk of AD in menopausal women by almost four times [23,24].”
From Effect of Caffeine Consumption on the Risk for Neurological and Psychiatric Disorders: Sex Differences in Human (2020) · cites this paper as [24]
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Metadata
- Authors
- Djelti, F., Braudeau, J., Hudry, E., Dhenain, M., Varin, J., Bièche, I., Marquer, C., Chali, F., Ayciriex, S., Auzeil, N., Alves, S., Langui, D., Potier, M.-C., Laprevote, O., Vidaud, M., Duyckaerts, C., Miles, R., Aubourg, P., & Cartier, N.
- Affiliations
- Université Paris-Sud (FR)
- Sorbonne Paris Cité (FR)
- Centre National de la Recherche Scientifique (FR)
- Lyon 1 Université (FR)
- Inserm (FR)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-07-02
- Volume
- 138
- Issue
- 8
- Pages
- 2383-2398
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2155858151
- Cited by
- 223
- References
- 62
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 26 · 2023: 31 · 2022: 21 · 2021: 28 · 2020: 17 · 2019: 23 · 2018: 16 · 2017: 9 · 2016: 12 · 2015: 3
- FWCI
- 9.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-11-INBS-0011)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- CYP46A1, cholesterol 24-hydroxylase, brain cholesterol homeostasis, Alzheimer's disease, hippocampal neurons, neuronal apoptosis, amyloid-beta, amyloid precursor protein, lipid rafts, tau phosphorylation, endoplasmic reticulum stress, hippocampal atrophy, cognitive impairment
- MeSH terms
- Cholesterol 24-Hydroxylase, Alzheimer Disease, Animals, Brain, Cholesterol, Enzyme Inhibitors, Female, Homeostasis, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Steroid Hydroxylases, Amyloid beta-Peptides, Amyloid beta-Protein Precursor
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