Apolipoprotein E4 (1–272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells
Open accessAbstract
BACKGROUND: Apolipoprotein E allele epsilon4 (apoE4) is a strong risk factor for developing Alzheimer's disease (AD). Secreted apoE has a critical function in redistributing lipids among central nervous system cells to maintain normal lipid homeostasis. In addition, previous reports have shown that apoE4 is cleaved by a protease in neurons to generate apoE4(1-272) fragment, which is associated with neurofibrillary tanglelike structures and mitochondria, causing mitochondrial dysfunction. However, it still remains unclear how the apoE fragment associates with mitochondria and induces mitochondrial dysfunction. RESULTS: To clarify the molecular mechanism, we carried out experiments to identify intracellular apoE-binding molecules and their functions in modulating mitochondria function. Here, we found that apoE4 binds to ubiquinol cytochrome c reductase core protein 2 (UQCRC2) and cytochrome C1, both of which are components of mitochondrial respiratory complex III, and cytochrome c oxidase subunit 4 isoform 1 (COX IV 1), which is a component of complex IV, in Neuro-2a cells. Interestingly, these proteins associated with apoE4(1-272) more strongly than intact apoE4(1-299). Further analysis showed that in Neuro-2a cells expressing apoE4(1-272), the enzymatic activities of mitochondrial respiratory complexes III and IV were significantly lower than those in Neuro-2a cells expressing apoE4(1-299). CONCLUSION: ApoE4(1-272) fragment expressed in Neuro2a cells is associated with mitochondrial proteins, UQCRC2 and cytochrome C1, which are component of respiratory complex III, and with COX IV 1, which is a member of complex IV. Overexpression of apoE4(1-272) fragment impairs activities of complex III and IV. These results suggest that the C-terminal-truncated fragment of apoE4 binds to mitochondrial complexes and affects their activities, and thereby leading to neurodegeneration.
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The largest apoE4 fragment, apoE4(1-272), interacts directly with mitochondria to reduce mitochondrial membrane potential.
“The largest apoE4 fragment, apoE4(1–272), interacts directly with mitochondria to reduce mitochondrial membrane potential”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [20]
The Results section on mitochondrial membrane potential (page unavailable) reports no significant difference between Neuro2a cells expressing apoE4(1–272) and control cells, contrary to the claimed reduction. The paper does report that the fragment associates with mitochondrial proteins and reduces respiratory-complex III and IV activity, but those findings do not establish a reduction in membrane potential. (LLM, conf=0.94)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAPOE4 expression generates a toxic C-terminal fragment of apoE4 that can directly target electron transport chain (ETC) complexes in mitochondria.
“the generation of a toxic C-terminal fragment of apoE4 that can directly target electron transport chain (ETC) complexes in the mitochondria25–27”
From APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice (2020) · cites this paper as [27]
The Conclusion (page not provided) reports that apoE4(1–272) associates with proteins in mitochondrial respiratory complexes III and IV and that its overexpression reduces their activities. The Background (page not provided) describes this as a C-terminal-truncated fragment—residues 1–272 remain—not a fragment consisting of apoE4’s C terminus. The paper also treats its direct binding to the complexes as a suggested mechanism. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe largest apoE4 fragment, apoE4(1-272), causes mitochondrial fragmentation.
“and cause mitochondrial fragmentation [10, 17, 20]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [20]
The Conclusion (page unavailable) reports that apoE4(1–272) expression in Neuro2a cells reduced the activities of mitochondrial respiratory complexes III and IV. This supports an effect on mitochondrial function, but the copy does not report mitochondrial fragmentation; searches for fragmentation and mitochondrial morphology found no such result. (LLM, conf=0.83)
Experimental — accuracy not yet measuredSeveral studies demonstrated a link between APOE4 and mitochondrial dysfunction, mainly in neurons.
“Several studies demonstrated a link between APOE4 and mitochondrial dysfunction, mainly in neurons9–11; yet the effect of APOE4 on mitochondrial dynamics was less studied.”
From Altered mitochondrial dynamics and function in APOE4-expressing astrocytes (2020) · cites this paper as [10]
ApoE fragments interact directly with mitochondria and disrupt their function.
“Although apoE fragments interact directly with mitochondria and disrupt their function [17, 20]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [20]
Under some transfection conditions, ApoE4 has no effect on Δψm.
“other authors demonstrated that, under some transfection conditions, ApoE4 has no effect on Δψm [75].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [75]
The APOE gene product appears to influence mitochondrial function.
“The APOE gene product, interestingly, also appears to influence mitochondrial function [164-167].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [167]
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- Authors
- Nakamura, T., Watanabe, A., Fujino, T., Hosono, T., & Michikawa, M.
- Affiliations
- National Center for Geriatrics and Gerontology (JP)
- Ehime University (JP)
- Corresponding author
- Michikawa, Makoto
- Venue
- Molecular Neurodegeneration
- Published
- 2009-08-20
- Volume
- 4
- Issue
- 1
- Pages
- 35-35
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC2739857
- OpenAlex
- W2115709331
- Cited by
- 124
- References
- 43
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 6 · 2023: 5 · 2022: 9 · 2021: 8 · 2020: 17 · 2019: 10 · 2018: 4 · 2017: 4 · 2016: 7 · 2015: 3 · 2014: 6 · 2013: 7 · 2012: 8
- FWCI
- 5.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (H20-007)
- National Institute of Biomedical Innovation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- APOE ε4, mitochondrial dysfunction, UQCRC2, cytochrome c1, respiratory complex III, respiratory complex IV, Alzheimer's disease, neurons, N2a cells, neurodegeneration
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