Cited by 226Alzheimer's disease research and treatmentsCholesterol and Lipid MetabolismNeuroinflammation and Neurodegeneration Mechanisms

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CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer’s disease

Djelti, Fathia, Braudeau, Jerome, Hudry, Eloise, Dhenain, Marc, Varin, Jennifer, Bièche, Ivan, Marquer, Catherine, Chali, Farah, Ayciriex, Sophie, Auzeil, Nicolas, Alves, Sandro, Langui, Dominique, Potier, Marie-Claude, Laprevote, Olivier, Vidaud, Michel, Duyckaerts, Charles, Miles, Richard, Aubourg, Patrick, Cartier, Nathalie·2015·Brain

DOI 10.1093/brain/awv166

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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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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: Djelti, Fathia
Varin, Jennifer
Bièche, Ivan
Marquer, Catherine
Chali, Farah
Ayciriex, Sophie
Alves, Sandro
Langui, Dominique
Potier, Marie-Claude
Duyckaerts, Charles
Miles, Richard
Cartier, Nathalie
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
DOI: 10.1093/brain/awv166
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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CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer’s disease

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