ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD
Open accessAbstract
Cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative diseases, including the abnormal accumulation of amyloid-beta, one of the pathological hallmarks of Alzheimer disease (AD). Acyl-CoA:cholesterol acyltransferases (ACAT1 and ACAT2) are two enzymes that convert free cholesterol to cholesteryl esters. ACAT inhibitors have recently emerged as promising drug candidates for AD therapy. However, how ACAT inhibitors act in the brain has so far remained unclear. Here we show that ACAT1 is the major functional isoenzyme in the mouse brain. ACAT1 gene ablation (A1-) in triple transgenic (i.e., 3XTg-AD) mice leads to more than 60% reduction in full-length human APPswe as well as its proteolytic fragments, and ameliorates cognitive deficits. At 4 months of age, A1- causes a 32% content increase in 24-hydroxycholesterol (24SOH), the major oxysterol in the brain. It also causes a 65% protein content decrease in HMG-CoA reductase (HMGR) and a 28% decrease in sterol synthesis rate in AD mouse brains. In hippocampal neurons, A1- causes an increase in the 24SOH synthesis rate; treating hippocampal neuronal cells with 24SOH causes rapid declines in hAPP and in HMGR protein levels. A model is provided to explain our findings: in neurons, A1- causes increases in cholesterol and 24SOH contents in the endoplasmic reticulum, which cause reductions in hAPP and HMGR protein contents and lead to amelioration of amyloid pathology. Our study supports the potential of ACAT1 as a therapeutic target for treating certain forms of AD.
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The technique employed for measuring in vivo cholesterol synthesis in whole brain or specific CNS regions has been utilized in several laboratories in an array of genetically altered mouse models.
“The technique employed for these measurements has been utilized in several laboratories for measuring, in vivo, the rate of cholesterol synthesis in either the whole brain, or specific regions of the CNS, in an array of genetically altered mouse models (Xie et al., 2003; Halford and Russell, 2009; Bryleva et al., 2010; Liu et al., 2010; Aqul et al., 2011; Suzuki et al., 2013).”
From Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis (2017) · cites this paper as Bryleva et al., 2010
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- Authors
- Bryleva, E. Y., Rogers, M. A., Chang, C. C. Y., Buen, F., Harris, B. T., Rousselet, E., Seidah, N. G., Oddo, S., LaFerla, F. M., Spencer, T. A., Hickey, W. F., & Chang, T.-Y.
- Affiliations
- Dartmouth College (US)
- Dartmouth–Hitchcock Medical Center (US)
- Montreal Clinical Research Institute (CA)
- The University of Texas at San Antonio Health Science Center (US)
- University of California, Irvine (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-01-26
- Volume
- 107
- Issue
- 7
- Pages
- 3081-3086
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2840286
- OpenAlex
- W2142555655
- Cited by
- 209
- References
- 7
- Citations by year
- 2026: 6 · 2025: 17 · 2024: 12 · 2023: 16 · 2022: 11 · 2021: 16 · 2020: 10 · 2019: 16 · 2018: 9 · 2017: 9 · 2016: 13 · 2015: 9 · 2014: 12 · 2013: 11 · 2012: 14
- FWCI
- 11.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- Dartmouth College
- National Yang-Ming University
- National Institutes of Health
- University of Illinois at Urbana-Champaign
- Canadian Institutes of Health Research (44363, MOP- 44363, MOP-36496)
- National Heart, Lung, and Blood Institute (HL 060306, R01HL060306)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- ACAT1, acyl-CoA:cholesterol acyltransferase, Alzheimer's disease, amyloid-beta, 24S-hydroxycholesterol, oxysterols, cholesterol metabolism, HMG-CoA reductase, APP processing, hippocampal neurons, endoplasmic reticulum cholesterol, ACAT inhibitors, gene ablation, cognitive impairment
- MeSH terms
- Acetyl-CoA C-Acetyltransferase, Acyl Coenzyme A, Alzheimer Disease, Amyloid, Animals, Brain, Cholesterol, Humans, Hydroxycholesterols, Mice, Transgenic, Models, Biological, Gene Silencing, Mice
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