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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]
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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“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
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 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]
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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]
The cited source says what the claim attributes to it.
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]
The cited source says what the claim attributes to it.
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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“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]
The cited source says what the claim attributes to it.
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]
The cited source says what the claim attributes to it.
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]
The cited source says what the claim attributes to it.
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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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Citations
Cites
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429
Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.5.1977 · Cited by 4,268
Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology
Mahley, R. W. (1988) · Science · doi:10.1126/science.3283935 · Cited by 4,028
Self-citationCellular uptake of the tat protein from human immunodeficiency virus
Frankel, A. D., & Pabo, C. O. (1988) · Cell · doi:10.1016/0092-8674(88)90263-2 · Cited by 2,782
In Vivo Protein Transduction: Delivery of a Biologically Active Protein into the Mouse
Schwarze, S. R., Ho, A. L., Vocero-Akbani, A. M., & Dowdy, S. F. (1999) · Science · doi:10.1126/science.285.5433.1569 · Cited by 2,418
Apolipoprotein E: Far More Than a Lipid Transport Protein
Mahley, R. W., & Rall, S. C. (2000) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.1.1.507 · Cited by 1,836
Self-citationGreen, M., & Loewenstein, P. M. (1988) · Cell · doi:10.1016/0092-8674(88)90262-0 · Cited by 1,551
Berridge, M. V., & Tan, A. S. (1993) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1993.1311 · Cited by 1,443
Mitochondrial abnormalities in Alzheimer's disease
Hirai, K., Aliev, G., Nunomura, A., Fujioka, H., Russell, R. L., Atwood, C. S., Johnson, A. B., Kress, Y., Vinters, H. V., Tabaton, M., et al. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-09-03017.2001 · Cited by 1,367
Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.17.8098 · Cited by 1,363
Research works printed but not linked: 1
- Wisniewski, T., Castaño, E. M., Golabek, A., Vogel, T. & Frangione, B. (1994) Am. J. Pathol. 145, 1030-1035.7977635
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Alzheimer Mechanisms and Therapeutic Strategies
Huang, Y., & Mucke, L. (2012) · Cell · doi:10.1016/j.cell.2012.02.040 · Cited by 1,758
Self-citationThe role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661
Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
Bu, G. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2620 · Cited by 1,168
Johnson, E. C. B., Dammer, E. B., Duong, D. M., Ping, L., Zhou, M., Yin, L., Higginbotham, L. A., Guajardo, A., White, B., Troncoso, J. C., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0815-6 · Cited by 1,001
Reddy, P. H., & Beal, M. F. (2008) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.12.002 · Cited by 975
Cogswell, J. P., Ward, J., Taylor, I. A., Waters, M., Shi, Y., Cannon, B., Kelnar, K., Kemppainen, J., Brown, D., Chen, C., et al. (2008) · Journal of Alzheimer s Disease · doi:10.3233/jad-2008-14103 · Cited by 943
Mahley, R. W., Weisgraber, K. H., & Huang, Y. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600549103 · Cited by 912
Self-citationMitochondria and Mitochondrial Cascades in Alzheimer’s disease
Swerdlow, R. H. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-170585 · Cited by 850
Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders
Mahley, R. W. (2016) · Journal of Molecular Medicine · doi:10.1007/s00109-016-1427-y · Cited by 837
Self-citationApolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases
Huang, Y., & Mahley, R. W. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.025 · Cited by 829
Self-citationThe Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.09.010 · Cited by 786
Risner, M. E., Saunders, A. M., Altman, J. F. B., Ormandy, G. C., Craft, S., Foley, I. M., Zvartau-Hind, M. E., Hosford, D. A., Roses, A. D., & for the Rosiglitazone in Alzheimer's Disease Study Group (2006) · The Pharmacogenomics Journal · doi:10.1038/sj.tpj.6500369 · Cited by 686
Age, APOE and sex: triad of risk of Alzheimer’s disease.
Riedel, B. C., Thompson, P. M., & Brinton, R. D. (2016) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2016.03.012 · Cited by 627
Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS
Mahley, R. W., Weisgraber, K. H., & Huang, Y. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r800069-jlr200 · Cited by 580
Self-citationThe Alzheimer’s Disease Mitochondrial Cascade Hypothesis
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100339 · Cited by 562
“tein E or its degradation products also appear to influence mitochondrial function [102].”
BackgroundReelin, lipoprotein receptors and synaptic plasticity
Herz, J., & Chen, Y. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn2009 · Cited by 524
Xu, Q., Bernardo, A., Walker, D., Kanegawa, T., Mahley, R. W., & Huang, Y. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.5476-05.2006 · Cited by 524
Self-citationCentral Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism
Mahley, R. W. (2016) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.116.307023 · Cited by 516
Self-citationCandidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease
Li, H., Wetten, S., Li, L., St. Jean, P. L., Upmanyu, R., Surh, L., Hosford, D., Barnes, M. R., Briley, J. D., Borrie, M., et al. (2008) · Archives of Neurology · doi:10.1001/archneurol.2007.3 · Cited by 499
ApoE4: an emerging therapeutic target for Alzheimer’s disease
Safieh, M., Korczyn, A. D., & Michaelson, D. M. (2019) · BMC Medicine · doi:10.1186/s12916-019-1299-4 · Cited by 449
Perez Ortiz, J. M., & Swerdlow, R. H. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14585 · Cited by 426
Apolipoprotein e sets the stage: response to injury triggers neuropathology
Mahley, R. W., & Huang, Y. (2012) · Neuron · doi:10.1016/j.neuron.2012.11.020 · Cited by 412
Self-citationA TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease
Roses, A. D., Lutz, M. W., Amrine‐Madsen, H., Saunders, A. M., Crenshaw, D. G., Sundseth, S. S., Huentelman, M. J., Welsh-Bohmer, K. A., & Reiman, E. M. (2009) · The Pharmacogenomics Journal · doi:10.1038/tpj.2009.69 · Cited by 391
Antioxidant Therapies for Alzheimer's Disease
Feng, Y., & Wang, X. (2012) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2012/472932 · Cited by 393
Oxidative Stress Signaling in Alzheimers Disease
Su, B., Wang, X., Nunomura, A., Moreira, P., Lee, H.-G., Perry, G., Smith, M., & Zhu, X. (2008) · Current Alzheimer Research · doi:10.2174/156720508786898451 · Cited by 344
Apolipoprotein E: From lipid transport to neurobiology
Hauser, P. S., Narayanaswami, V., & Ryan, R. O. (2011) · Progress in Lipid Research · doi:10.1016/j.plipres.2010.09.001 · Cited by 320
A mitochondrial etiology of Alzheimer and Parkinson disease
Coskun, P. E., Wyrembak, J., Schriner, S. E., Chen, H.-W., Marciniack, C., LaFerla, F. M., & Wallace, D. C. (2011) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2011.08.008 · Cited by 297
Li, G., Bien-Ly, N., Andrews-Zwilling, Y., Xu, Q., Bernardo, A., Ring, K., Halabisky, B., Deng, C., Mahley, R. W., & Huang, Y. (2009) · Cell Stem Cell · doi:10.1016/j.stem.2009.10.015 · Cited by 288
Self-citationOxidative stress and β-amyloid protein in Alzheimer’s disease
Cai, Z., Zhao, B., & Ratka, A. (2011) · NeuroMolecular Medicine · doi:10.1007/s12017-011-8155-9 · Cited by 279
Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer’s disease
Atamna, H., & Frey, W. H. (2007) · Mitochondrion · doi:10.1016/j.mito.2007.06.001 · Cited by 278
Pathogenesis of Alzheimer's disease.
Swerdlow, R. H. (2007) · PubMed · Cited by 242
Juszczyk, G., Mikulska, J., Kasperek, K., Pietrzak, D., Mrozek, W., & Herbet, M. (2021) · Antioxidants · doi:10.3390/antiox10091439 · Cited by 247
Apolipoprotein E and Alzheimer’s disease: Findings, hypotheses, and potential mechanisms
Koutsodendris, N., Nelson, M. R., Rao, A., & Huang, Y. (2022) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-030421-112756 · Cited by 231
Self-citationBossers, K., Wirz, K. T. S., Meerhoff, G. F., Essing, A. H. W., van Dongen, J. W., Houba, P., Kruse, C. G., Verhaagen, J., & Swaab, D. F. (2010) · Brain · doi:10.1093/brain/awq258 · Cited by 230
Mitochondrial Medicine for Aging and Neurodegenerative Diseases
Reddy, P. H. (2008) · NeuroMolecular Medicine · doi:10.1007/s12017-008-8044-z · Cited by 230
The Genetic Variability of APOE in Different Human Populations and Its Implications for Longevity
Abondio, P., Sazzini, M., Garagnani, P., Boattini, A., Monti, D., Franceschi, C., Luiselli, D., & Giuliani, C. (2019) · Genes · doi:10.3390/genes10030222 · Cited by 240
Uddin, M. S., Kabir, M. T., Al Mamun, A., Abdel-Daim, M. M., Barreto, G. E., & Ashraf, G. M. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1237-z · Cited by 212
Chen, H.-K., Ji, Z.-S., Dodson, S. E., Miranda, R. D., Rosenblum, C. I., Reynolds, I. J., Freedman, S. B., Weisgraber, K. H., Huang, Y., & Mahley, R. W. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.151084 · Cited by 209
Self-citationThe Alzheimer's disease mitochondrial cascade hypothesis: an update
Swerdlow, R. H., & Khan, S. M. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.01.011 · Cited by 206
Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease
Cioffi, F., Adam, R. H. I., & Broersen, K. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190863 · Cited by 204
“ance of A [240, 241], mitochondrial dysfunction, 972 and impairment of calcium [242, 243] or cellular 973 iron homeostasis [244], and ApoE4 affects synaptic 974 architecture and functioning [245, 246].”
BackgroundMitochondria in Neurodegeneration
Lezi, E., & Swerdlow, R. H. (2011) · Advances in experimental medicine and biology · doi:10.1007/978-94-007-2869-1_12 · Cited by 213
Swerdlow, R. H. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4149 · Cited by 206
Oxidized cholesterol as the driving force behind the development of Alzheimer’s disease
Gamba, P., Testa, G., Gargiulo, S., Staurenghi, E., Poli, G., & Leonarduzzi, G. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00119 · Cited by 180
Molecular links between Alzheimer’s disease and diabetes mellitus
Yang, Y., & Song, W. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.07.009 · Cited by 211
Multifaceted roles of APOE in Alzheimer disease
Jackson, R. J., Hyman, B. T., & Serrano-Pozo, A. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00988-2 · Cited by 193
Dragicevic, N., Mamcarz, M. B., Zhu, Y., Buzzeo, R. W., Tan, J., Arendash, G. W., & Bradshaw, P. C. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100342 · Cited by 197
Dragicevic, N., Smith, A., Lin, X., Yuan, F., Copes, N., Delic, V., Tan, J., Cao, C., Shytle, R. D., & Bradshaw, P. C. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101629 · Cited by 192
Apolipoprotein E and oxidative stress in brain with relevance to Alzheimer's disease
Butterfield, D. A., & Mattson, M. P. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104795 · Cited by 190
Wu, L., Zhang, X., & Zhao, L. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.2262-17.2018 · Cited by 185
Ramanan, V. K., & Saykin, A. J. (2013) · Europe PMC (PubMed Central) · Cited by 190
Dragicevic, N., Copes, N., O’Neal-Moffitt, G., Jin, J., Buzzeo, R. W., Mamcarz, M., Tan, J., Cao, C., Olcese, J., Arendash, G. W., et al. (2011) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2011.00864.x · Cited by 185
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Najm, R., Jones, E. A., & Huang, Y. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0324-6 · Cited by 183
Self-citationPalop, J. J., & Mucke, L. (2009) · NeuroMolecular Medicine · doi:10.1007/s12017-009-8097-7 · Cited by 183
Pharmacogenetics in drug discovery and development: a translational perspective
Roses, A. D. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2593 · Cited by 177
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Huang, Y. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.04.004 · Cited by 170
Self-citationYamazaki, Y., Painter, M. M., Bu, G., & Kanekiyo, T. (2016) · CNS Drugs · doi:10.1007/s40263-016-0361-4 · Cited by 173
Chen, H.-K., Liu, Z., Meyer-Franke, A., Brodbeck, J., Miranda, R. D., McGuire, J. G., Pleiss, M. A., Ji, Z.-S., Balestra, M. E., Walker, D. W., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.276162 · Cited by 163
Self-citationCoskun, P. E., Wyrembak, J., Derbereva, O., Melkonian, G., Doran, E. W., Lott, I. T., Head, E., Cotman, C. W., & Wallace, D. C. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100351 · Cited by 161
Pires, M., & Rego, A. C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24010778 · Cited by 157
Ullah, R., Khan, M., Shah, S. A., Saeed, K. M., & Kim, M. O. (2019) · Nutrients · doi:10.3390/nu11061195 · Cited by 158
Valla, J., Yaari, R., Wolf, A. B., Kusne, Y., Beach, T. G., Roher, A. E., Corneveaux, J. J., Huentelman, M. J., Caselli, R. J., & Reiman, E. M. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100129 · Cited by 150
Tzioras, M., Davies, C., Newman, A., Jackson, R., & Spires‐Jones, T. (2019) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12529 · Cited by 147
Kim, J., Yoon, H., Basak, J., & Kim, J. (2014) · Molecules and Cells · doi:10.14348/molcells.2014.0248 · Cited by 141
“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).”
BackgroundAPOE genotype and stress response - a mini review
Dose, J., Huebbe, P., Nebel, A., & Rimbach, G. (2016) · Lipids in Health and Disease · doi:10.1186/s12944-016-0288-2 · Cited by 137
Atherosclerosis and Alzheimer - diseases with a common cause? Inflammation, oxysterols, vasculature
Lathe, R., Tsitrina, A. A., & Kotelevtsev, Y. V. (2014) · BMC Geriatrics · doi:10.1186/1471-2318-14-36 · Cited by 141
Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene
Boehm-Cagan, A., & Michaelson, D. M. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.5198-13.2014 · Cited by 134
Mahley, R. W., & Huang, Y. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm3008618 · Cited by 132
Self-citationZhang, J., Cao, Q., Li, S., Lu, X., Zhao, Y., Guan, J., Chen, J., Wu, Q., & Chen, G. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.06.043 · Cited by 130
Genetic architecture of Alzheimer's disease
Neuner, S. M., TCW, J., & Goate, A. M. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104976 · Cited by 126
“nervous system, APOEε4 has been linked to impaired Aβ clearance [71, 72], disruption of lysosomes and neuronal apoptosis [73, 74], as well as mitochondrial dysfunction [75].”
BackgroundNakamura, T., Watanabe, A., Fujino, T., Hosono, T., & Michikawa, M. (2009) · Molecular Neurodegeneration · doi:10.1186/1750-1326-4-35 · Cited by 124
Epigenomics of Alzheimer's disease
Bennett, D. A., Yu, L., Yang, J., Srivastava, G. P., Aubin, C., & Jager, P. L. D. (2014) · Translational research · doi:10.1016/j.trsl.2014.05.006 · Cited by 126
Mitochondrial dysfunction and Alzheimer's disease
Maruszak, A., & Żekanowski, C. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.07.004 · Cited by 124
Intron-3 Retention/Splicing Controls Neuronal Expression of Apolipoprotein E in the CNS
Xu, Q., Walker, D., Bernardo, A., Brodbeck, J., Balestra, M. E., & Huang, Y. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.3253-07.2008 · Cited by 122
Self-citationAn inherited variable poly-T repeat genotype in TOMM40 in Alzheimer disease
Roses, A. D. (2010) · Archives of Neurology · doi:10.1001/archneurol.2010.88 · Cited by 118
New Insights in the Amyloid-Beta Interaction with Mitochondria
Spuch, C., Ortolano, S., & Fernández-Balbuena, C. N. (2012) · Journal of Aging Research · doi:10.1155/2012/324968 · Cited by 121
The Thiazolidinedione Pioglitazone Alters Mitochondrial Function in Human Neuron-Like Cells
Ghosh, S., Patel, N., Rahn, D. A., McAllister, J., Sadeghi, S., Horwitz, G., Berry, D., Wang, K. X., & Swerdlow, R. H. (2007) · Molecular Pharmacology · doi:10.1124/mol.106.033845 · Cited by 119
Brodbeck, J., McGuire, J., Liu, Z., Meyer-Franke, A., Balestra, M. E., Jeong, D.-E., Pleiss, M., McComas, C., Hess, F., Witter, D., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.217380 · Cited by 113
Self-citationApoE and Neurodegenerative Diseases in Aging
Yin, Y., & Wang, Z. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-1117-8_5 · Cited by 111
Peng, Y., Gao, P., Shi, L., Chen, L., Liu, J., & Long, J. (2020) · Antioxidants & Redox Signaling · doi:10.1089/ars.2019.7763 · Cited by 110
Fišar, Z. (2022) · Biomolecules · doi:10.3390/biom12111676 · Cited by 113
Caselli, R. J., & Reiman, E. M. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-129026 · Cited by 111
Roses, A. D., Saunders, A. M., Huang, Y., Strum, J. C., Weisgraber, K. H., & Mahley, R. W. (2006) · The Pharmacogenomics Journal · doi:10.1038/sj.tpj.6500397 · Cited by 109
Self-citationAPOE alters glucose flux through central carbon pathways in astrocytes
Williams, H. C., Farmer, B. C., Piron, M. A., Walsh, A. E., Bruntz, R. C., Gentry, M. S., Sun, R. C., & Johnson, L. A. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104742 · Cited by 105
Orr, A. L., Kim, C., Jimenez-Morales, D., Newton, B. W., Johnson, J. R., Krogan, N. J., Swaney, D. L., & Mahley, R. W. (2019) · Journal of Alzheimer's Disease · doi:10.3233/jad-181184 · Cited by 103
Self-citationThe cell biology of APOE in the brain
Windham, I. A., & Cohen, S. (2024) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.09.004 · Cited by 103
Hesse, R., Hurtado, M. L., Jackson, R. J., Eaton, S. L., Herrmann, A. G., Colom-Cadena, M., Tzioras, M., King, D., Rose, J., Tulloch, J., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0847-7 · Cited by 107
Slow Excitotoxicity in Alzheimer's Disease
Ong, W.-Y., Tanaka, K., Dawe, G. S., Ittner, L. M., & Farooqui, A. A. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-121990 · Cited by 106
Hoogmartens, J., Cacace, R., & Broeckhoven, C. V. (2021) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12155 · Cited by 109
Genetic variation at a single locus and age of onset for Alzheimer's disease
Lutz, M. W., Crenshaw, D. G., Saunders, A. M., & Roses, A. D. (2010) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2010.01.011 · Cited by 101
Newington, J. T., Harris, R. A., & Cumming, R. C. (2013) · Journal of Neurodegenerative Diseases · doi:10.1155/2013/234572 · Cited by 109
Mitochondria in Alzheimer's disease and their potential role in Alzheimer's proteostasis
Weidling, I. W., & Swerdlow, R. H. (2020) · Experimental Neurology · doi:10.1016/j.expneurol.2020.113321 · Cited by 104
Gout and the risk of dementia: a nationwide population-based cohort study
Hong, J.-Y., Lan, T.-Y., Tang, G., Tang, C., Chen, T., & Lin, H.-Y. (2015) · Arthritis Research & Therapy · doi:10.1186/s13075-015-0642-1 · Cited by 100
Huang, R. Y.-C., Garai, K., Frieden, C., & Gross, M. L. (2011) · Biochemistry · doi:10.1021/bi2010027 · Cited by 97
Apolipoprotein E4 produced in GABAergic interneurons causes learning and memory deficits in mice
Knoferle, J., Yoon, S. Y., Walker, D., Leung, L., Gillespie, A. K., Tong, L. M., Bien-Ly, N., & Huang, Y. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.2281-14.2014 · Cited by 97
Self-citationAPOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size
Windham, I. A., Powers, A. E., Ragusa, J. V., Wallace, E. D., Zanellati, M. C., Williams, V. H., Wagner, C. H., White, K. K., & Cohen, S. (2024) · Journal of Cell Biology · doi:10.1083/jcb.202305003 · Cited by 96
Disentangling Mitochondria in Alzheimer’s Disease
Johri, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111520 · Cited by 103
Amyloid precursor protein and mitochondrial dysfunction in Alzheimer's disease
Anandatheerthavarada, H. K., & Devi, L. (2007) · The Neuroscientist · doi:10.1177/1073858407303536 · Cited by 95
Roles of ApoE4 on the Pathogenesis in Alzheimer’s Disease and the Potential Therapeutic Approaches
Sun, Y.-Y., Wang, Z., & Huang, H. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01365-1 · Cited by 102
Bello‐Chavolla, O. Y., Antonio‐Villa, N. E., Vargas‐Vázquez, A., Ávila‐Funes, J. A., & Aguilar-Salinas, C. A. (2019) · Current Diabetes Reviews · doi:10.2174/1573399815666190129155654 · Cited by 96
Alzheimer’s Disease and Cholesterol: The Fat Connection
Canevari, L., & Clark, J. B. (2006) · Neurochemical Research · doi:10.1007/s11064-006-9200-1 · Cited by 97
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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