Cholesterol Defect Is Marked across Multiple Rodent Models of Huntington's Disease and Is Manifest in Astrocytes
Open accessAbstract
Brain cholesterol, which is synthesized locally, is a major component of myelin and cell membranes and participates in neuronal functions, such as membrane trafficking, signal transduction, neurotransmitter release, and synaptogenesis. Here we show that brain cholesterol biosynthesis is reduced in multiple transgenic and knock-in Huntington's disease (HD) rodent models, arguably dependent on deficits in mutant astrocytes. Mice carrying a progressively increased number of CAG repeats show a more evident reduction in cholesterol biosynthesis. In postnatal life, the cholesterol-dependent activities of neurons mainly rely on the transport of cholesterol from astrocytes on ApoE-containing particles. Our data show that mRNA levels of cholesterol biosynthesis and efflux genes are severely reduced in primary HD astrocytes, along with impaired cellular production and secretion of ApoE. Consistently, in CSF of HD mice, ApoE is mostly associated with smaller lipoproteins, indicating reduced cholesterol transport on ApoE-containing lipoproteins circulating in the HD brain. These findings indicate that cholesterol defect is robustly marked in HD animals, implying that strategies aimed at selectively modulating brain cholesterol metabolism might be of therapeutic significance.
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Astrocyte-dependent cholesterol dysregulation is implicated in several neurological disorders, including Fragile X syndrome, Alzheimer's disease and Huntington's disease.
“Our findings are consistent with growing evidence implicating astrocyte-dependent cholesterol dysregulation in several neurological disorders, including Fragile X syndrome, Alzheimer's disease and Huntington's disease (Ren et al., 2023;Valenza et al., 2010).”
From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Valenza et al., 2010
The Discussion reports impaired cholesterol metabolism in mutant astrocytes and says astrocyte-involving mechanisms may contribute to the cholesterol defect in Huntington's disease brains. The paper does not address astrocyte-dependent cholesterol dysregulation in Fragile X syndrome or Alzheimer's disease, so it supports only the Huntington's disease portion of the cited sentence. (LLM, conf=0.86)
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Cites
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Cholesterol metabolism in neurons and astrocytes
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Neuroinflammation in Huntington’s Disease: A Starring Role for Astrocyte and Microglia
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Modulation of Brain Cholesterol Metabolism through CYP46A1 Overexpression for Rett Syndrome
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Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome
Postogna, F. M., Giancroce, N., Cabasino, C., Biella, F., Roggero, O. M., Breccia, M., Morelli, L., Colombo, D., Arcari, A., Lunghi, G., et al. (2026) · doi:10.64898/2026.07.29.741426 · Cited by 1 · see citing works
“Our findings are consistent with growing evidence implicating astrocyte-dependent cholesterol dysregulation in several neurological disorders, including Fragile X syndrome, Alzheimer's disease and Huntington's disease (Ren et al., 2023; Valenza et al., 2010).”
Self-citation
- Authors
- Valenza, M., Leoni, V., Karasinska, J. M., Petricca, L., Fan, J., Carroll, J., Pouladi, M. A., Fossale, E., Nguyen, H. P., Riess, O., MacDonald, M., Wellington, C., DiDonato, S., Hayden, M., & Cattaneo, E.
- Affiliations
- University of Milan (IT)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- University of British Columbia (CA)
- Harvard University (US)
- University of Tübingen (DE)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-08-11
- Volume
- 30
- Issue
- 32
- Pages
- 10844-10850
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3842469
- OpenAlex
- W2009959558
- Cited by
- 166
- References
- 3
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 10 · 2023: 16 · 2022: 6 · 2021: 9 · 2020: 8 · 2019: 13 · 2018: 6 · 2017: 6 · 2016: 11 · 2015: 17 · 2014: 10 · 2013: 7 · 2012: 13
- FWCI
- 5.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Funders
- CHDI Foundation
- European Commission
- Fondazione Cariplo
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS32765, R01NS032765)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- Huntington's disease, astrocytes, apolipoprotein E, cholesterol transport, CAG repeat expansion, cholesterol efflux, cholesterol metabolism, transgenic mouse model
- MeSH terms
- Analysis of Variance, Animals, Animals, Newborn, Apolipoproteins E, Astrocytes, Brain, Cells, Cultured, Cholesterol, Disease Models, Animal, Myelin Basic Protein, Female, Huntington Disease, Male, Myelin Sheath, Sterols, Synaptosomes, Trinucleotide Repeat Expansion, Animals, Genetically Modified, Synaptosomal-Associated Protein 25, Mice, Rats
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