Independent effects of APOE on cholesterol metabolism and brain A levels in an Alzheimer disease mouse model
Abstract
The APOE epsilon4 allele is the most significant genetic risk factor associated with Alzheimer's disease to date. Epidemiological studies have demonstrated that inheritance of one or more epsilon4 alleles affects both the age of onset and the severity of pathology development. Dosage of APOE epsilon2 and epsilon3 alleles, however, appear to be protective against the effects of epsilon4. Although much of the biology of APOE in peripheral cholesterol metabolism is understood, its role in brain cholesterol metabolism and its impact on AD development is less defined. Several APOE transgenic models have been generated to study the effects of APOE alleles on APP processing and Abeta pathology. However, these models have potential limitations that confound our understanding of the effects of apolipoprotein E (APOE) levels and cholesterol metabolism on disease development. To circumvent these limitations, we have taken a genomic-based approach to better understand the relationship between APOE alleles, cholesterol and Abeta metabolism. We have characterized APOE knock-in mice, which express each human allele under the endogenous regulatory elements, on a defined C57BL6/J background. These mice have significantly different serum cholesterol levels and steady-state brain APOE levels, and yet have equivalent brain cholesterol levels. However, the presence of human APOE significantly increases brain Abeta levels in a genomic-based model of AD, irrespective of genotype. These data indicat…
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Several subsequent studies were able to detect a genotype-dependent difference in apoE levels (E2>E3>E4) in the brain and CSF of apoE knock-in mice.
“However, several subsequent studies were able to detect a genotype-dependent difference in apoE levels (E2>E3>E4) in the brain and CSF of apoE knock-in mice (Fryer et al., 2005a; Mann et al., 2004; Ramaswamy et al., 2005; Riddell et al., 2008; Vitek et al., 2007).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Mann et al., 2004
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The role of apolipoprotein E in Alzheimer's disease
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Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels
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Manf/ewsr1/anxa6 pathway might as the bridge between hypolipidemia and major depressive disorder
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- Authors
- Mann, K. M.
- Affiliations
- Case Western Reserve University (US)
- Corresponding author
- Mann, K. M.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-06-30
- Volume
- 13
- Issue
- 17
- Pages
- 1959-1968
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2128998014
- Cited by
- 48
- References
- 5
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 5 · 2023: 2 · 2022: 7 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 1 · 2015: 1 · 2014: 2 · 2012: 2
- FWCI
- 1.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institute on Aging (P50AG008012, R01AG014451)
- National Heart, Lung, and Blood Institute (R01HL032868)
- National Cancer Institute (CA 43703, P30CA043703)
- National Institute of General Medical Sciences (GM-08613, T32GM008613)
- 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
- apolipoprotein E, APOE ε4, Alzheimer's disease, brain cholesterol metabolism, amyloid-beta, serum cholesterol, genetic risk factors, APP processing
- MeSH terms
- Alleles, Alzheimer Disease, Animals, Apolipoproteins E, Brain, Cholesterol, Enzyme-Linked Immunosorbent Assay, Mice, Transgenic, Triglycerides, Blotting, Western, Amyloid beta-Peptides, Genetic Predisposition to Disease, Mice
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