Homocysteine, Another Risk Factor for Alzheimer Disease, Impairs Apolipoprotein E3 Function
Open accessAbstract
Apolipoprotein E (apoE) ε4 and hyperhomocysteinemia are risk factors for Alzheimer disease (AD). The dimerization of apoE3 by disulfide bonds between cysteine residues enhances apoE3 function to generate HDL. Because homocysteine (Hcy) harbors a thiol group, we examined whether Hcy interferes with the dimerization of apoE3 and thereby impairs apoE3 function. We found that Hcy inhibits the dimerization of apoE3 and reduces apoE3-mediated HDL generation to a level similar to that by apoE4, whereas Hcy does not affect apoE4 function. Western blot analysis of cerebrospinal fluid showed that the ratio of apoE3 dimers was significantly lower in the samples from the patients with hyperhomocysteinemia than in those that from control subjects. Hyperhomocysteinemia induced by subcutaneous injection of Hcy to apoE3 knock-in mice decreased the level of the apoE3 dimer in the brain homogenate. Because apoE-HDL plays a role in amyloid β-protein clearance, these results suggest that two different risk factors, apoE4 and hyperhomocysteinemia, may share a common mechanism that accelerates the pathogenesis of AD in terms of reduced HDL generation.
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Cysteine-dependent ApoE3 homodimers and ApoE3-apoA-II complexes have been linked to HDL-related behavior and redox buffering.
“These cysteine-dependent ApoE3 homodimers and ApoE3-apoA-II complexes have been linked to HDL-related behavior and redox buffering (44,45), and plasma ApoE homodimer levels are reduced in APOEε3-carrying AD patients relative to controls (43), suggesting that these disulfide-linked species may themselves be functionally relevant in ways not captured by the NanoBiT assay.”
From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [44]
The Results and Discussion link cysteine-dependent apoE3 dimerization to cholesterol efflux and HDL generation. The passages do not address apoE3–apoA-II complexes or redox buffering, so those parts of the attributed claim are unsupported by this source. (LLM, conf=0.87)
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Cites
ApoE Promotes the Proteolytic Degradation of Aβ
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apoE isoform–specific disruption of amyloid β peptide clearance from mouse brain
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Research works printed but not linked: 2
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Andrieieva, D., Falltrick, I., Chiang, C.-Y., Beaumont, B., Guen, Y. L., Liu, C., Pergolesi, S., Ma, C.-T., Jackson, M. R., Hyman, B. T., et al. (2026) · doi:10.64898/2026.05.09.26352797 · Cited by 2 · see citing works
- Authors
- Minagawa, H., Watanabe, A., Akatsu, H., Adachi, K., Ohtsuka, C., Terayama, Y., Hosono, T., Takahashi, S., Wakita, H., Jung, C.-G., Komano, H., & Michikawa, M.
- Affiliations
- National Center for Geriatrics and Gerontology (JP)
- Fukushimura Hospital (JP)
- Iwate Medical University (JP)
- Corresponding author
- Michikawa, Makoto
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 285
- Issue
- 49
- Pages
- 38382-38388
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2992271
- OpenAlex
- W2084783700
- Cited by
- 40
- References
- 7
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 5 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 2 · 2013: 3 · 2012: 8
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (H20-007)
- National Institute of Biomedical Innovation
- Japan Society for the Promotion of Science (20023040)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- homocysteine, hyperhomocysteinemia, Alzheimer's disease, apolipoprotein E3, APOE ε4, disulfide bonds, amyloid-beta clearance, cerebrospinal fluid, risk factors
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disulfides, Homocysteine, Humans, Lipoproteins, HDL, Risk Factors, Amyloid beta-Peptides, Mice, Knockout, Hyperhomocysteinemia, Mice, Apolipoprotein E3, Apolipoprotein E4, Protein Multimerization
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