Effect of Domain Interaction on Apolipoprotein E Levels in Mouse Brain
Open accessAbstract
Apolipoprotein (apo) E4 is a risk factor for heart disease, Alzheimer's disease, and other forms of neurodegeneration, but the underlying mechanisms are unknown. Domain interaction, a structural property that distinguishes apoE4 from apoE2 and apoE3, results in more rapid turnover and lower plasma levels of apoE4. To determine whether domain interaction affects brain apoE levels, we analyzed brain homogenates from human apoE3 and apoE4 knock-in mice, wild-type mice, and Arg-61 apoE mice, in which domain interaction was introduced by gene targeting. As determined on Western blots, the hemibrain, cortex, hippocampus, and cerebellum of knock-in mice had 30-40% lower levels of apoE4 than apoE3, and Arg-61 mice had 25-50% lower apoE levels than wild-type mice. In the CSF, Arg-61 apoE level was 40% lower than the wild-type level. Arg-61 apoE mRNA levels were similar to or slightly higher than wild-type apoE mRNA levels. Thus, the lower Arg-61 apoE levels were not attributable to decreased mRNA levels. In culture medium from heterozygous Arg-61/wild-type and apoE4/apoE3 primary astrocytes, Arg-61 apoE and apoE4 levels were lower than wild-type apoE and apoE3, respectively, suggesting that primary astrocytes secrete lower amounts of Arg-61 apoE and apoE4. These results demonstrate that domain interaction is responsible for the lower levels of both human apoE4 and mouse Arg-61 apoE in mouse brain. Cells may recognize apoE4 and Arg-61 apoE as misfolded proteins and target them for degradation or accumulation. Thus, degradation/accumulation or lower levels of apoE4 may contribute to the association of apoE4 with Alzheimer's disease.
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A detergent-rich lysis buffer has been shown to inhibit apoE oligomerization and fully release lipid-bound apoE epitopes that, if not exposed, may hamper accurate detection of apoE levels by immunoassay.
“Such a detergent-rich lysis buffer has been shown to inhibit apoE oligomerization and fully release the lipid-bound apoE epitopes which, if not exposed, may hamper accurate detection of apoE levels by immunoassay (Krul and Cole, 1996;Ramaswamy et al., 2005).”
From Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels (2008) · cites this paper as Ramaswamy et al., 2005
The Discussion says detergents remove bound lipid, making apoE epitopes available to antibodies, and that unexposed epitopes can affect immunoassay results. It separately says denaturing conditions prevent oligomerization; it does not establish that the detergent-rich lysis buffer alone does so. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPreferential degradation of apoE4 relative to apoE3 in astrocytes leads to a reduced capacity for delivery of cholesterol to neurons for repair.
“the preferential degradation of apoE4 relative to apoE3 in astrocytes leads to a reduced capacity for the delivery of cholesterol the neurons for repair”
From Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels (2008) · cites this paper as Ramaswamy et al., 2005
The astrocyte-culture results (page not provided) show less apoE4 than apoE3 in conditioned medium. The Discussion (page not provided) proposes degradation of apoE4 in astrocytes as a possibility, not an established cause. The paper does not report reduced cholesterol delivery to neurons for repair, so the claimed consequence is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSeveral 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 Ramaswamy et al., 2005
The Results section (“Lower brain levels of apoE4 than apoE3 in human knock-in mice”; page not specified in our copy) reports lower apoE4 than apoE3 levels in knock-in mouse brains. It does not establish the full E2>E3>E4 ranking. The CSF measurements described in the Discussion and Methods concern Arg-61 versus wild-type mouse apoE, not E2, E3, and E4 in human apoE knock-in mice. (LLM, conf=0.90)
Experimental — accuracy not yet measuredEngineering an apoE4-like Arg-61 domain interaction into murine apoE affects CNS apoE biology and leads to low brain levels of apoE.
“Recently, Ramaswamy et al. (2005) published data to suggest that engineering an apoE4-like, Arg-61 domain interaction into murine apoE also affects CNS apoE biology and leads to low brain levels of apoE.”
From Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels (2008) · cites this paper as Ramaswamy et al. (2005)
Detergent extraction of plasma, CSF, and brain samples before quantification precluded well-known issues of apolipoprotein detection in aqueous solutions.
“We also detergent extracted plasma, CSF and brain samples before quantification, thus precluding well known issues of apolipoprotein detection in aqueous solutions (Krul and Cole, 1996;Ramaswamy et al., 2005).”
From Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels (2008) · cites this paper as Ramaswamy et al., 2005
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- Authors
- Ramaswamy, G., Xu, Q., Huang, Y., & Weisgraber, K. H.
- Affiliations
- University of California, San Francisco (US)
- Gladstone Institutes (US)
- Corresponding author
- Weisgraber, Karl H.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-11-16
- Volume
- 25
- Issue
- 46
- Pages
- 10658-10663
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725862
- OpenAlex
- W2000039441
- Cited by
- 87
- References
- 7
- Citations by year
- 2025: 4 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 7 · 2015: 2 · 2014: 3 · 2013: 1 · 2012: 8
- FWCI
- 1.80
- 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)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1c06rr018928-01)
- National Institute on Aging (AG-20235, R01AG020235)
- National Heart, Lung, and Blood Institute (HL 37063, R01HL037063)
- National Center for Research Resources (C06-RR-018928)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- apolipoprotein E, APOE ε4, domain interactions, cerebrospinal fluid, Alzheimer's disease, protein misfolding, protein degradation, APOE isoforms
- MeSH terms
- Animals, Apolipoproteins E, Brain, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, RNA, Messenger, Protein Structure, Tertiary, Mice, Apolipoprotein E3, Apolipoprotein E4
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