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Cited by 54Mitochondrial Function and PathologyAlzheimer's disease research and treatmentsEndoplasmic Reticulum Stress and Disease

ApoE4 (Δ272–299) induces mitochondrial‐associated membrane formation and mitochondrial impairment by enhancing GRP75-modulated mitochondrial calcium overload in neuron

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Liang, Tao, Hang, Weijian, Chen, Jiehui, Wu, Yue, Wen, Bin, Xu, Kai, Ding, Bingbing, Chen, Juan·2021·Cell & Bioscience
DOI 10.1186/s13578-021-00563-yPMC PMC7937300
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Abstract

Background: Apolipoprotein E4 (apoE4) is a major genetic risk factor of Alzheimer’s disease. Its C-terminal-truncated apoE4 (Δ272–299) has neurotoxicity by affecting mitochondrial respiratory function. However, the molecular mechanism(s) underlying the action of apoE4 (Δ272–299) in mitochondrial function remain poorly understood. Methods: The impact of neuronal apoE4 (Δ272–299) expression on ER stress, mitochondrial-associated membrane (MAM) formation, GRP75, calcium transport and mitochondrial impairment was determined in vivo and in vitro. Furthermore, the importance of ER stress or GRP75 activity in the apoE4 (Δ272–299)-promoted mitochondrial dysfunction in neuron was investigated. Results: Neuronal apoE4 (Δ272–299) expression induced mitochondrial impairment by inducing ER stress and mitochondrial-associated membrane (MAM) formation in vivo and in vitro. Furthermore, apoE4 (Δ272–299) expression promoted GRP75 expression, mitochondrial dysfunction and calcium transport into the mitochondria in neuron, which were significantly mitigated by treatment with PBA (an inhibitor of ER stress), MKT077 (a specific GRP75 inhibitor) or GRP75 silencing. Conclusions: ApoE4 (Δ272–299) significantly impaired neuron mitochondrial function by triggering ER stress, up-regulating GRP75 expression to increase MAM formation, and mitochondrial calcium overload. Our findings may provide new insights into the neurotoxicity of apoE4 (Δ272–299) against mitochondrial function and uncover new therapeutic targets for the intervention of Alzheimer’s disease.

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  • ApoE4 fragments (aa 273-299) are associated with changes in mitochondrial dynamics and morphology, ER stress, decreased ATP production and mitochondrial membrane potential, and increased ROS levels in N2a cells.

    “more recently it has been demonstrated that these ApoE4 fragments are associated to changes in mitochondrial dynamics and morphology, endoplasmic reticulum (ER) stress, decreased ATP production and mitochondrial membrane potential (Δψm) and increased ROS levels, in N2a cells [28].”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [28]

    The Results sections on ER stress, mitochondrial morphology and function, and fusion and fission report all the stated changes in N2a cells expressing apoE4 (Δ272–299). The fragment designation is the exception: the Introduction says cleavage at Met 272 produces apoE4 (Δ272–299), meaning a fragment lacking the C-terminal residues, not a fragment consisting of amino acids 273–299. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Other studies demonstrated association between ApoE4 and fission activation and fusion inhibition.

    “other studies demonstrated an association between ApoE4 and fission activation and fusion inhibition [28]”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [28]

    The Results section reports that overexpression of ApoE4 (Δ272–299) increased pro-fission activity and decreased pro-fusion activity in transgenic mouse hippocampus and N2a cells. The citing sentence omits the Δ272–299 truncation and presents the finding as applying to ApoE4 generally; this paper's reported experiment does not establish that broader claim. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • ApoE4 (272-299 aa fragment) increases ROS levels in N2a cell line.

    “ApoE4 (272–299 aa fragment) was demonstrated to increase ROS levels in N2a cell line [28,73]”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [28]

    The Results section, “ApoE4 (Δ272–299) changes mitochondrial morphology and function,” reports significantly increased ROS in N2a cells expressing apoE4 (Δ272–299). The Introduction identifies this as a C-terminally truncated apoE4 fragment produced by cleavage at residue 272, not a fragment consisting of amino acids 272–299. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • This increase in ROS levels correlates with increased ER stress and enhanced MAM formation by favoring mitochondria-ER direct interaction.

    “which was shown to correlate with increased ER stress and enhanced MAM formation by favoring mitochondria-ER direct interaction [28].”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [28]

  • Association between ApoE4 expression and mitochondrial Ca2+ overload was observed in in vitro models, such as Neuro-2 A cells, stem-cell-derived forebrain excitatory neurons and rat hippocampal neurons.

    “an association between ApoE4 expression and mitochondrial Ca2+ overload was observed in in vitro models, such as Neuro-2 A cells [28,73], stem-cell-derived forebrain excitatory neurons [50] and rat hippocampal neurons [30].”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [28]

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Research works printed but not linked: 47

  1. [1]Kim JH Oho AUID- Genetics of Alzheimer’s Disease Dement Neurocogn Disord 2018 17 131 6 10.12779/dnd.2018.17.4.131 30906402 PMC6425887 · DOI
  2. [3]Corder EH Saunders AM Strittmatter WJ Schmechel DE Gaskell PC Small GW Roses AD Haines JL Pericak-Vance MA Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families Science 1993 261 921 3 10.1126/science.8346443 8346443 · DOI · Paper page
  3. [4]Tesseur I Van Dorpe J Spittaels K Van den Haute C Moechars D Van Leuven F Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice Am J Pathol 2000 156 951 64 10.1016/S0002-9440(10)64963-2 10702411 PMC1876840 · DOI
  4. [5]Tesseur I Van Dorpe J Bruynseels K Bronfman F Sciot R Van Lommel A Van Leuven F Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord Am J Pathol 2000 157 1495 510 10.1016/S0002-9440(10)64788-8 11073810 PMC1885744 · DOI
  5. [6]Brecht WJ Harris FM Chang S Tesseur I Yu GQ Xu Q Dee FJ Wyss-Coray T Buttini M Mucke L Mahley RW Huang Y Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice J Neurosci 2004 24 2527 34 10.1523/JNEUROSCI.4315-03.2004 15014128 PMC6729489 · DOI · Paper page
  6. [7]Huang Y Liu XQ Wyss-Coray T Brecht WJ Sanan DA Mahley RW Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons Proc Natl Acad Sci U S A 2001 98 8838 43 10.1073/pnas.151254698 11447277 PMC37522 · DOI · Paper page
  7. [8]Atamna H Frey WH 2nd Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer’s disease Mitochondrion 2007 7 297 310 10.1016/j.mito.2007.06.001 17625988 · DOI · Paper page
  8. [9]Parihar MS Brewer GJ Mitoenergetic failure in Alzheimer disease Am J Physiol Cell Physiol 2007 292 C8 23 10.1152/ajpcell.00232.2006 16807300 · DOI
  9. [10]Friedland-Leuner K Stockburger C Denzer I Eckert GP Muller WE Mitochondrial dysfunction: cause and consequence of Alzheimer’s disease Prog Mol Biol Transl Sci 2014 127 183 210 10.1016/B978-0-12-394625-6.00007-6 25149218 · DOI
  10. [11]Chen HK Ji ZS Dodson SE Miranda RD Rosenblum CI Reynolds IJ Freedman SB Weisgraber KH Huang Y Mahley RW Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease J Biol Chem 2011 286 5215 21 10.1074/jbc.M110.151084 21118811 PMC3037634 · DOI · Paper page
  11. [12]Perkins M Wolf AB Chavira B Shonebarger D Meckel JP Leung L Ballina L Ly S Saini A Jones TB Vallejo J Jentarra G Valla J Altered Energy Metabolism Pathways in the Posterior Cingulate in Young Adult Apolipoprotein E varepsilon4 Carriers J Alzheimers Dis 2016 53 95 106 10.3233/JAD-151205 27128370 PMC4942726 · DOI
  12. [13]Nakamura T Watanabe A Fujino T Hosono T Michikawa M Apolipoprotein E4 (1-272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells Mol Neurodegener 2009 4 35 10.1186/1750-1326-4-35 19695092 PMC2739857 · DOI · Paper page
  13. [14]Vance JE MAM (mitochondria-associated membranes) in mammalian cells: lipids and beyond Biochim Biophys Acta 2014 1841 595 609 10.1016/j.bbalip.2013.11.014 24316057 · DOI
  14. [15]Hayashi T Su TP Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival Cell 2007 131 596 610 10.1016/j.cell.2007.08.036 17981125 · DOI · Paper page
  15. [16]Verfaillie T Rubio N Garg AD Bultynck G Rizzuto R Decuypere JP Piette J Linehan C Gupta S Samali A Agostinis P PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress Cell Death Differ 2012 19 1880 91 10.1038/cdd.2012.74 22705852 PMC3469056 · DOI
  16. [18]Veeresh P Kaur H Sarmah D Mounica L Verma G Kotian V Kesharwani R Kalia K Borah A Wang X Dave KR Rodriguez AM Yavagal DR Bhattacharya P Endoplasmic reticulum-mitochondria crosstalk: from junction to function across neurological disorders Ann NY Acad Sci 2019 1457 41 60 10.1111/nyas.14212 31460675 · DOI
  17. [19]Area-Gomez E de Groof A Bonilla E Montesinos J Tanji K Boldogh I Pon L Schon EA A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease Cell Death Dis 2018 9 335 10.1038/s41419-017-0215-0 29491396 PMC5832428 · DOI · Paper page
  18. [20]Volgyi K Juhasz G Kovacs Z Penke B Dysfunction of Endoplasmic Reticulum (ER) and Mitochondria (MT) in Alzheimer’s Disease: The Role of the ER-MT Cross-Talk Curr Alzheimer Res 2015 12 655 72 10.2174/1567205012666150710095035 26159206 · DOI
  19. [21]Area-Gomez E Schon EA On the Pathogenesis of Alzheimer’s Disease: The MAM Hypothesis FASEB J 2017 31 864 7 10.1096/fj.201601309 28246299 PMC6191063 · DOI
  20. [22]Leal NS Schreiner B Pinho CM Filadi R Wiehager B Karlstrom H Pizzo P Ankarcrona M Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid beta-peptide production J Cell Mol Med 2016 20 1686 95 10.1111/jcmm.12863 27203684 PMC4988279 · DOI
  21. [23]Liang J Kulasiri D Samarasinghe S Ca2 + dysregulation in the endoplasmic reticulum related to Alzheimer’s disease: A review on experimental progress and computational modeling Biosystems 2015 134 1 15 10.1016/j.biosystems.2015.05.003 25998697 · DOI
  22. [24]Supnet C Bezprozvanny I Neuronal calcium signaling, mitochondrial dysfunction, and Alzheimer’s disease J Alzheimers Dis 2010 20 Suppl 2 487-98 PMC4996661 20413848
  23. [25]Schon EA Area-Gomez E Is Alzheimer’s disease a disorder of mitochondria-associated membranes J Alzheimers Dis 2010 20 Suppl 2 281-92 20421691
  24. [26]Szabadkai G Bianchi K Varnai P De Stefani D Wieckowski MR Cavagna D Nagy AI Balla T Rizzuto R Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2 + channels J Cell Biol 2006 175 901 11 10.1083/jcb.200608073 17178908 PMC2064700 · DOI · Paper page
  25. [27]Honrath B, Metz I, Bendridi N, Rieusset J, Culmsee C, Dolga AM. Glucose-regulated protein 75 determines ER-mitochondrial coupling and sensitivity to oxidative stress in neuronal cells. Cell Death Discov 2017;3:17076. PMC5672593 29367884
  26. [28]Arun S Liu L Donmez G Mitochondrial Biology and Neurological Diseases Curr Neuropharmacol 2016 14 143 54 10.2174/1570159X13666150703154541 26903445 PMC4825945 · DOI
  27. [29]Petrozzi L Ricci G Giglioli NJ Siciliano G Mancuso M Mitochondria and neurodegeneration Biosci Rep 2007 27 87 104 10.1007/s10540-007-9038-z 17486441 · DOI
  28. [30]Moreira PI Zhu X Wang X Lee HG Nunomura A Petersen RB Perry G Smith MA Mitochondria: a therapeutic target in neurodegeneration Biochim Biophys Acta 2010 1802 212 20 10.1016/j.bbadis.2009.10.007 19853657 PMC2790540 · DOI
  29. [31]Szabadkai G Bianchi K Varnai P De Stefani D Wieckowski MR Cavagna D Nagy AI Balla T Rizzuto R Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2 + channels J Cell Biol 2006 175 901 11 10.1083/jcb.200608073 17178908 PMC2064700 · DOI · Paper page
  30. [32]Belinson H Kariv-Inbal Z Kayed R Masliah E Michaelson DM Following activation of the amyloid cascade, apolipoprotein E4 drives the in vivo oligomerization of amyloid-beta resulting in neurodegeneration J Alzheimers Dis 2010 22 959 70 10.3233/JAD-2010-101008 20858958 PMC5051636 · DOI
  31. [33]Paroni G Bisceglia P Seripa D Understanding the Amyloid Hypothesis in Alzheimer’s Disease J Alzheimers Dis 2019 68 493 510 10.3233/JAD-180802 30883346 · DOI
  32. [37]Montagne A Oho AUID- Nation DA Sagare AP Barisano G Oho AUID- Sweeney MD Chakhoyan A Pachicano M Joe E Nelson AR D’Orazio LM Buennagel DP Harrington MG TLS B Fagan AM Ringman JM Schneider LS Morris JC Reiman EM Oho AUID- Caselli RJ Chui HC Tcw J Oho AUID- Chen Y Pa J Conti PS Law M Toga AW Zlokovic BV Oho AUID- APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline Nature 2020 581 71 6 10.1038/s41586-020-2247-3 32376954 PMC7250000 · DOI · Paper page
  33. [38]He K, Nie L, Zhou Q, Rahman SU, Liu J, Yang X, Li S. Proteomic profiles of the early mitochondrial changes in APP/PS1 and ApoE4 transgenic mice models of Alzheimer’s Disease. J Proteome Res 2019;18:2632–2642. 31055927
  34. [39]James R Searcy JL Le BT Martin SF Gliddon CM Povey J Deighton RF Kerr LE McCulloch J Horsburgh K Proteomic analysis of mitochondria in APOE transgenic mice and in response to an ischemic challenge J Cereb Blood Flow Metab 2012 32 164 76 10.1038/jcbfm.2011.120 21878944 PMC3323298 · DOI
  35. [40]Chen HK Ji ZS Dodson SE Miranda RD Rosenblum CI Reynolds IJ Freedman SB Weisgraber KH Huang Y Mahley RW Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease J Biol Chem 2011 286 5215 21 10.1074/jbc.M110.151084 21118811 PMC3037634 · DOI · Paper page
  36. [41]Verderio C Matteoli M ATP in neuron-glia bidirectional signalling Brain Res Rev 2011 66 106 14 10.1016/j.brainresrev.2010.04.007 20451555 · DOI
  37. [43]Huang Y Liu XQ Wyss-Coray T Brecht WJ Sanan DA Mahley RW Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons Proc Natl Acad Sci U S A 2001 98 8838 43 10.1073/pnas.151254698 11447277 PMC37522 · DOI · Paper page
  38. [44]Xiang C Wang Y Zhang H Han F The role of endoplasmic reticulum stress in neurodegenerative disease Apoptosis 2017 22 1 26 10.1007/s10495-016-1296-4 27815720 · DOI
  39. [45]Liang T Xue F Hang W Wen B Zhang Q Chen J Liu X Chen J Neuron-Specific Apolipoprotein E4 (1-272) Fragment Induces Tau Hyperphosphorylation and Axonopathy via Triggering Endoplasmic Reticulum Stress J Alzheimers Dis 2019 71 597 611 10.3233/JAD-190419 31424401 · DOI
  40. [46]Tambini MD Pera M Kanter E Yang H Guardia-Laguarta C Holtzman D Sulzer D Area-Gomez E Schon EA ApoE4 upregulates the activity of mitochondria-associated ER membranes EMBO Rep 2016 17 27 36 10.15252/embr.201540614 26564908 PMC4718413 · DOI · Paper page
  41. [47]Rusinol AE Cui Z Chen MH Vance JE A unique mitochondria-associated membrane fraction from rat liver has a high capacity for lipid synthesis and contains pre-Golgi secretory proteins including nascent lipoproteins J Biol Chem 1994 269 27494 502 10.1016/S0021-9258(18)47012-3 7961664 · DOI
  42. [48]Gelmetti V De Rosa P Torosantucci L Marini ES Romagnoli A Di RM Arena G Vignone D Fimia GM Valente EM PINK1 and BECN1 relocalize at mitochondria-associated membranes during mitophagy and promote ER-mitochondria tethering and autophagosome formation Autophagy 2017 13 654 69 10.1080/15548627.2016.1277309 28368777 PMC5388214 · DOI
  43. [49]Szymanski J, Janikiewicz J, Michalska B, Patalas-Krawczyk P, Perrone M, Ziolkowski W, Duszynski J, Pinton P, Dobrzyn A, Wieckowski MR. Interaction of Mitochondria with the Endoplasmic Reticulum and Plasma Membrane in Calcium Homeostasis, Lipid Trafficking and Mitochondrial Structure. Int J Mol Sci. 2017;18. PMC5536064 28726733
  44. [50]Halestrap AP Calcium, mitochondria and reperfusion injury: a pore way to die Biochem Soc Trans 2006 34 232 7 10.1042/BST0340232 16545083 · DOI
  45. [51]Luongo TS Lambert JP Yuan A Zhang X Gross P Song J Shanmughapriya S Gao E Jain M Houser SR Koch WJ Cheung JY Madesh M Elrod JW The Mitochondrial Calcium Uniporter Matches Energetic Supply with Cardiac Workload during Stress and Modulates Permeability Transition Cell Rep 2015 12 23 34 10.1016/j.celrep.2015.06.017 26119731 PMC4517182 · DOI · Paper page
  46. [53]Itoh K Nakamura K Iijima M Sesaki H Mitochondrial dynamics in neurodegeneration Trends Cell Biol 2013 23 64 71 10.1016/j.tcb.2012.10.006 23159640 PMC3558617 · DOI
  47. [54]El-Hattab AW Suleiman J Almannai M Scaglia F Mitochondrial dynamics: Biological roles, molecular machinery, and related diseases Mol Genet Metab 2018 125 315 21 10.1016/j.ymgme.2018.10.003 30361041 · DOI

Cited by

Sorted by citations

Authors
Liang, T., Hang, W., Chen, J., Wu, Y., Wen, B., Xu, K., Ding, B., & Chen, J.
Affiliations
  • Wuhan Union Hospital (CN)
  • Tongji Hospital (CN)
  • Huazhong University of Science and Technology (CN)
Corresponding author
Chen, Juan
ORCID
Venue
Cell & Bioscience
Publisher
Springer Science and Business Media LLC
Published
2021-03-06
Volume
11
Issue
1
Pages
50-50
ISSN
2045-3701 (ISSN-L)
DOI
10.1186/s13578-021-00563-y
PMC
PMC7937300
OpenAlex
W3135070800
Cited by
54
References
7
Citations by year
2026: 14 · 2025: 11 · 2024: 9 · 2023: 8 · 2022: 9 · 2021: 3
FWCI
2.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell & Bioscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (31670778, 81873725)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
APOE ε4, Alzheimer's disease, mitochondrial dysfunction, mitochondria-associated membranes, GRP75, endoplasmic reticulum stress, mitochondrial calcium overload, PBA, mitochondrial calcium transport

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