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Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity
Open accessAbstract
Apolipoprotein (apo) E4, a 299-aa protein and a major risk factor for Alzheimer's disease, can be cleaved to generate C-terminal-truncated fragments that cause neurotoxicity in vitro and neurodegeneration and behavioral deficits in transgenic mice. To investigate this neurotoxicity, we expressed apoE4 with C- or N-terminal truncations or mutations in transfected Neuro-2a cells. ApoE4 (1-272) was neurotoxic, but full-length apoE4(1-299) and apoE4(1-240) were not, suggesting that the lipid-binding region (amino acids 241-272) mediates the neurotoxicity and that amino acids 273-299 are protective. A quadruple mutation in the lipid-binding region (I250A, F257A, W264R, and V269A) abolished the neurotoxicity of apoE4(1-272), and single mutations in the region of amino acids 273-299 (L279Q, K282A, or Q284A) made full-length apoE4 neurotoxic. Immunofluorescence staining showed that apoE4(1-272) formed filamentous inclusions containing phosphorylated tau in some cells and interacted with mitochondria in others, leading to mitochondrial dysfunction as determined by MitoTracker staining and flow cytometry. ApoE4(241-272) did not cause mitochondrial dysfunction or neurotoxicity, suggesting that the lipid-binding region alone is insufficient for neurotoxicity. Truncation of N-terminal sequences (amino acids 1-170) containing the receptor-binding region (amino acids 135-150) and triple mutations within that region (R142A, K146A, and R147A) abolished the mitochondrial interaction and neurotoxicity of apoE4(1-272). Further analysis showed that the receptor-binding region is required for escape from the secretory pathway and that the lipid-binding region mediates mitochondrial interaction. Thus, the lipid- and receptor-binding regions in apoE4 fragments act together to cause mitochondrial dysfunction and neurotoxicity, which may be important in Alzheimer's disease pathogenesis.
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“APOE4 increases the sensitivity of cells to oxidative stress”
From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [13]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“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 [25]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“On the molecular level, ApoE4 has been associated with aggravated AD neuropathology, enhanced neuroinflammation, deregulated lipid metabolism, mitochondrial dysfunction, and impaired synaptic plasticity (Nagy et al., 1995;Chang et al., 2005;Rapp et al., 2006;Klein et al., 2010;Rodriguez et al., 2014).”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Chang et al., 2005
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“expression of fragments containing this domain in N2a cells results in neurotoxicity [17]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“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 [17]
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“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 [17]
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“In neurons, apoE4 is associated with impaired mitochondrial respiration”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Studies on the trafficking of APOE have also suggested that the cleaved C-terminus of APOE can exist in the cytoplasm and associate with mitochondria in neurons (Chang et al., 2005).”
From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Chang et al., 2005
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“and in higher levels than in age- and sex-matched controls [29].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [29]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“ApoE4 largest fragment (1–272 aa) was shown to directly interact with mitochondria, which leads to a decrease in Δψm and mitochondrial fragmentation [26,29,73].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [29]
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“Limited data suggest that a particular fragment of apoE (1–272 amino acids) can translocate to cytosol and interacts with cytoskeletal proteins (Chang et al., 2005).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Chang et al., 2005
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In the citing paper
“These and other findings suggest that not all apoE4 forms found in the brains of AD patients are equally bioactive and that specific apoE4 forms may be involved in processes associated with AD pathogenesis (10, 14 -17).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [16]
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“In vitro studies have shown that fragments of APOE, which are more abundant with APOE4 than with APOE3, can cause neuronal mitochondrial dysfunction165,166.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [165]
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In the citing paper
“apoE4 (1-272) fragment appears to interact directly with mitochondria, resulting in mitochondrial dysfunction and neurotoxicity [13]”
From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [13]
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“Available literature also shows that apoE4 (1-272) fragments can directly interact with mitochondria, causing mitochondrial dysfunction and neurotoxicity [13].”
From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [13]
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In the citing paper
“The resulting apoE fragments escape the secretory pathway into the cytosol”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
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In the citing paper
“and neurotoxicity [10, 17–19, 34, 35]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
The cited source says what the claim attributes to it.
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“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 [17]
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In the citing paper
“The interaction of apoE4 fragments with mitochondria is dependent on the apoE lipid-binding domain”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
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In the citing paper
“where they engage in abnormal interactions that lead to neurodegeneration [17–19]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
The cited source says what the claim attributes to it.
In the citing paper
“some studies in N2a cells demonstrated that ApoE4 N-terminal fragments (1–272 aa) interact with mitochondria and may possibly impact on mitochondrial function and cell viability [29]”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [29]
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“Both regions are thought to be critical for ApoE4 fragment-related neurotoxicity and mitochondrial impairment, rather than full-length protein [29,31].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [29]
The cited source says what the claim attributes to it.
In the citing paper
“In vitro studies in N2a cells showed that ApoE4 fragments (aa 1–272) interact with mitochondria and cause mitochondrial dysfunction and neurotoxicity [29].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [29]
The cited source says what the claim attributes to it.
In the citing paper
“Of note, more recent data suggests the possibility that a fragment of apoE4 (1–272 amino acids), but not full-length apoE4, escapes the secretory pathway, translocates to the cytosolic compartment, and interacts with cytoskeletal components, including tau and neurofilament (Chang et al., 2005).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Chang et al., 2005
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In the citing paper
“decreased neurite outgrowth”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
Experimental — accuracy not yet measuredIn the citing paper
“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 [164]
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Metadata
- Authors
- Chang, S., Ma, T. R., Miranda, R. D., Balestra, M. E., Mahley, R. W., & Huang, Y.
- Affiliations
- University of California, San Francisco (US)
- Gladstone Institutes (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-12-12
- Volume
- 102
- Issue
- 51
- Pages
- 18694-18699
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1311737
- OpenAlex
- W2022943683
- Cited by
- 319
- References
- 73
- Citations by year
- 2026: 16 · 2025: 8 · 2024: 15 · 2023: 16 · 2022: 14 · 2021: 14 · 2020: 16 · 2019: 21 · 2018: 13 · 2017: 14 · 2016: 18 · 2015: 10 · 2014: 15 · 2013: 19 · 2012: 18
- FWCI
- 7.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- GlaxoSmithKline
- National Institutes of Health (AG‐022074)
- National Institute on Aging (P01AG022074)
- National Heart, Lung, and Blood Institute (R01 HL37063, R01HL037063)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- APOE ε4, neurotoxicity, mitochondrial dysfunction, receptor-binding region, Alzheimer's disease, tau phosphorylation, N2a cells, transgenic mice
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Cytoskeleton, Lipids, Mitochondria, Mutation, Neurons, Peptide Fragments, Receptors, Lipoprotein, Cell Line, Tumor, Mice, Apolipoprotein E4
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