Why lipids are important for Alzheimer disease?
Abstract
Several lines of evidence suggest that dysregulated lipid metabolism may participate in the pathogenesis of Alzheimer's disease (AD). Epidemiologic studies suggest that elevated mid-life plasma cholesterol levels may be associated with an increased risk of AD and that statin use may reduce the prevalence of AD. Cellular studies have shown that the levels and distribution of intracellular cholesterol markedly affect the processing of amyloid precursor protein into A beta peptides, which are the toxic species that accumulate as amyloid plaques in the AD brain. Most importantly, genetic evidence identifies apolipoprotein E, the major cholesterol carrier in the central nervous system, as the primary genetic risk factor for sporadic AD. In humans, apoE exists as three major alleles (apoE2, apoE3, and apoE4), and inheritance of the apoE4 allele increases the risk of developing AD at an earlier age. However, exactly how apoE functions in the pathogenesis of AD remains to be fully determined. Our studies have identified that the cholesterol transporter ABCA1 is a crucial regulator of apoE levels and lipidation in the brain. Deficiency of ABCA1 leads to the loss of approximately 80% of apoE in the brain, and the residual 20% that remains is poorly lipidated. Several independent studies have shown this poorly lipidated apoE increases amyloid burden in mouse models of AD, demonstrating that apoE lipidation by ABCA1 affects key steps in amyloid deposition or clearance. Conversely, robust…
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ABCA1 is a cholesterol transporter that transfers excess cellular cholesterol onto lipid-poor apolipoproteins.
“ATP-binding cassette transporter A1 (ABCA1) is a cholesterol transporter that transfers excess cellular cholesterol onto lipid-poor apolipoproteins.”
From miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression (2012) · cites this paper as Hirsch-Reinshagen et al., 2009
The brain is the most cholesterol-rich organ in the body, containing ~25% of total body cholesterol.
“The brain is the most cholesterol-rich organ in the body, containing ~25% of total body cholesterol [73].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [73]
ApoE is the major cholesterol carrier in the central nervous system; in the brain, lipids are transported on HDL-like particles where apoE is the primary apolipoprotein, unlike in the circulation where apoA1 is primary and apoE is present at lower levels.
“ApoE is the major cholesterol carrier in the central nervous system: in the brain, lipids are transported on lipoproteins that resemble HDL particles, but while apolipoprotein A1 (apoA1) is the primary apolipoprotein and apoE is present in lower levels in HDL in the circulation, in contrast apoE is the primary apolipoprotein on these HDL-like particles found in the brain [67,73,75].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [73]
ABCA1 regulates apoE levels and lipidation in the brain; in mice, ABCA1 deficiency leads to loss of apoE with residual apoE being poorly lipidated, whereas overexpression promotes apoE lipidation and reduces amyloid plaque formation.
“ABCA1 regulates apoE levels and lipidation of apoE in the brain; in mice, deficiency of ABCA1 leads to loss of apoE with residual apoE being poorly lipidated; in contrast, overexpression of ABCA1 promotes apoE lipidation and reduces formation of amyloid plaques [73].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [73]
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References 109 · Cited by 86
- Authors
- Hirsch-Reinshagen, V., Burgess, B. L., & Wellington, C. L.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- Wellington, Cheryl L.
- Venue
- Molecular and Cellular Biochemistry
- Published
- 2008-12-31
- Volume
- 326
- Issue
- 1-2
- Pages
- 121-129
- ISSN
- 0300-8177 (ISSN-L)
- 1573-4919
- OpenAlex
- W2052555803
- Cited by
- 86
- References
- 109
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 7 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 6 · 2017: 5 · 2016: 5 · 2015: 3 · 2014: 3 · 2013: 9 · 2012: 9
- FWCI
- 5.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Molecular and Cellular Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, lipid metabolism, cholesterol, apolipoprotein E, APOE ε4, ABCA1, APP processing, amyloid plaques, amyloid deposition, statins, serum cholesterol, genetic risk factors
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Cholesterol, Humans, Lipids, Models, Biological, Peptide Fragments, Amyloid beta-Peptides, ATP-Binding Cassette Transporters, Mice
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