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Cited by 59Mitochondrial Function and PathologyAlzheimer's disease research and treatmentsAutophagy in Disease and Therapy

The Effects of APOE4 on Mitochondrial Dynamics and Proteins in vivo

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Simonovitch, Shira, Schmukler, Eran, Masliah, Eliezer, Pinkas-Kramarski, Ronit, Michaelson, Daniel M.·2019·Journal of Alzheimer's Disease
DOI 10.3233/jad-190074PMC PMC7478177
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Abstract

This study examined the effects of apolipoprotein E4 (APOE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), on proteins involved in mitochondrial dynamics and autophagy, in the hippocampus of targeted replacement mice. Immunohistochemical measurements revealed that the levels of the mitochondrial fusion-mediating protein, MFN1, were higher, whereas those of corresponding fission-regulating protein, DRP-1, were lower in the hippocampus of ApoE4 mice than in the corresponding ApoE3 mice, indicating that APOE4 is associated with increased mitochondrial fusion and decreased fission. A similar ApoE4-driven decrease in DRP-1 was also observed in AD brains. The levels of the mitochondrial proteins COX1 and Tom40, were higher in the ApoE4 mice, which is consistent with the increased fusion. Measurements of the levels of cleaved PINK1 and parkin, which mark and target mitochondria for mitophagic degradation, revealed lower levels of cleaved PINK1, suggesting reduced mitochondrial membrane potential, and higher levels of parkin in the hippocampus of ApoE4 compared with the ApoE3 mice, indicating altered mitophagy. The levels of the ubiquitin-binding scaffold protein, p62/SQSTM1, which directs selected cargo to the autophagosomes, were also higher in the ApoE4 mice. These findings suggest that APOE4 is associated with enhanced mitochondrial fusion and decreased fission. Additionally, the results indicate that mitophagy/autophagy is reduced in ApoE4 mice, resulting in higher levels of proteins such as parkin and p62, which are normally degraded during this process. Taken together, these results suggest a novel mechanism that may underlie the pathological effects of APOE4 and indicate that use of APOE4 genotyping could pave the way for identification of novel APOE4-related therapeutic targets.

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  1. [1]Roses AD, Saunders AM, Alberts MA, Strittmatter WJ, Schmechel D, Gorder E, Pericak-Vance MA (1995) Apolipoprotein E E4 allele and risk of dementia. JAMA 273, 374– 375; author reply 375–376. 7823377
  2. [4]Bu G (2009) Apolipoprotein E and its receptors in Alzheimer’s disease: Pathways, pathogenesis and therapy. Nat Rev Neurosci 10, 333– 344. 19339974 PMC2908393
  3. [5]Strittmatter WJ, Roses AD (1996) Apolipoprotein E and Alzheimer’s disease. Annu Rev Neurosci 19, 53– 77. 8833436
  4. [6]Cortopassi GA, Wong A(1999) Mitochondria in organismal aging and degeneration. Biochim Biophys Acta 1410, 183193. 10076026
  5. [7]Parker WD Jr, Mahr NJ, Filley CM, Parks JK, Hughes D, Young DA, Cullum CM (1994) Reduced platelet cytochrome c oxidase activity in Alzheimer’s disease. Neurology 44, 1086– 1090. 8208406
  6. [8]Krishnan KJ, Ratnaike TE, De Gruyter HL, Jaros E, Turnbull DM (2012) Mitochondrial DNA deletions cause the biochemical defect observed in Alzheimer’s disease. Neurobiol Aging 33, 2210– 2214. 21925769
  7. [9]Wilkins HM, Koppel SJ, Bothwell R, Mahnken J, Burns JM, Swerdlow RH (2017) Platelet cytochrome oxidase and citrate synthase activities in APOE epsilon4 carrier and noncarrier Alzheimer’s disease patients. Redox Biol 12, 828832. PMC5406545 28448944
  8. [10]Muller WE, Eckert A, Kurz C, Eckert GP, Leuner K (2010) Mitochondrial dysfunction: Common final pathway in brain aging and Alzheimer’s disease–therapeutic aspects. Mol Neurobiol 41, 159– 171. 20461558
  9. [11]Lee J, Goh LK, Chen G, Verma S, Tan CH, Lee TS (2012) Analysis of blood-based gene expression signature in first-episode psychosis. Psychiatry Res 200, 52– 54. 22503327
  10. [12]Manczak M, Jung Y, Park BS, Partovi D, Reddy PH (2005) Time-course of mitochondrial gene expressions in mice brains: Implications for mitochondrial dysfunction, oxidative damage, and cytochrome c in aging. J Neurochem 92, 494– 504. 15659220
  11. [13]Sultana R, Boyd-Kimball D, Poon HF, Cai J, Pierce WM, Klein JB, Merchant M, Markesbery WR, Butterfield DA (2006) Redox proteomics identification of oxidized proteins in Alzheimer’s disease hippocampus and cerebellum: An approach to understand pathological and biochemical alterations in AD. Neurobiol Aging 27, 1564– 1576. 16271804
  12. [14]Perry G, Nunomura A, Hirai K, Takeda A, Aliev G, Smith MA (2000) Oxidative damage in Alzheimer’s disease: The metabolic dimension. Int J Dev Neurosci 18, 417– 421. 10817925
  13. [15]Gibson GE, Haroutunian V, Zhang H, Park LC, Shi Q, Lesser M, Mohs RC, Sheu RK, Blass JP (2000) Mitochondrial damage in Alzheimer’s disease varies with apolipoprotein E genotype. Ann Neurol 48, 297– 303. 10976635
  14. [16]Luque-Contreras D, Carvajal K, Toral-Rios D, Franco-Bocanegra D, Campos-Pena V (2014) Oxidative stress and metabolic syndrome: Cause or consequence of Alzheimer’s disease? Oxid Med Cell Longev 2014, 497802. 24683436 PMC3941786
  15. [17]Kubli DA, Gustafsson AB (2012) Mitochondria and mitophagy: The yin and yang of cell death control. Circ Res 111, 1208– 1221. 23065344 PMC3538875
  16. [18]Itoh K, Nakamura K, Iijima M, Sesaki H (2013) Mitochondrial dynamics in neurodegeneration. Trends Cell Biol 23, 64– 71. 23159640 PMC3558617
  17. [19]Manczak M, Calkins MJ, Reddy PH (2011) Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer’s disease: Implications for neuronal damage. Hum Mol Genet 20, 2495– 2509. 21459773 PMC3109997
  18. [20]Silva DF, Selfridge JE, Lu J, E L, Cardoso SM, Swerdlow RH (2012) Mitochondrial abnormalities in Alzheimer’s disease: Possible targets for therapeutic intervention. Adv Pharmacol 64, 83– 126. 22840745 PMC3625400
  19. [22]Manczak M, Kandimalla R, Yin X, Reddy PH (2018) Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer’s disease. Hum Mol Genet 27, 13321342. PMC6455948 29408999
  20. [23]Du F, Yu Q, Yan S, Hu G, Lue LF, Walker DG, Wu L, Yan SF, Tieu K, Yan SS (2017) PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer’s disease. Brain 140, 3233– 3251. 29077793 PMC5841141
  21. [24]Ye X, Sun X, Starovoytov V, Cai Q (2015) Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer’s disease patient brains. Hum Mol Genet 24, 2938– 2951. 25678552 PMC4406302
  22. [25]Hong X, Liu J, Zhu G, Zhuang Y, Suo H, Wang P, Huang D, Xu J, Huang Y, Yu M, Bian M, Sheng Z, Fei J, Song H, Behnisch T, Huang F (2014) Parkin overexpression ameliorates hippocampal long-term potentiation and beta-amyloid load in an Alzheimer’s disease mouse model. Hum Mol Genet 23, 1056– 1072. 24105468
  23. [27]Salminen A, Kaarniranta K, Haapasalo A, Hiltunen M, Soininen H, Alafuzoff I (2012) Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer’s disease. Prog Neurobiol 96, 87– 95. 22138392
  24. [28]Tanji K, Maruyama A, Odagiri S, Mori F, Itoh K, Kakita A, Takahashi H, Wakabayashi K (2013) Accumulation of autophagic adaptor protein, p62/sequestosome 1, in the brains of Alzheimer’s disease. Front Immunol Conference Abstract:15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00680 · DOI
  25. [30]Simonovitch S, Schmukler E, Bespalko A, Iram T, Frenkel D, Holtzman DM, Masliah E, Michaelson DM, Pinkas-Kramarski R (2016) Impaired autophagy in ApoE4 astrocytes. J Alzheimers Dis 51, 915– 927. 26923027
  26. [31]Schmukler E, Michaelson DM, Pinkas-Kramarski R (2018) The interplay between apolipoprotein E4 and the autophagic-endocytic-lysosomal axis. Mol Neurobiol 55, 6863– 6880. 29353455
  27. [32]Parcon PA, Balasubramaniam M, Ayyadevara S, Jones RA, Liu L, Shmookler Reis RJ, Barger SW, Mrak RE, Griffin WST (2018) Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs. Alzheimers Dement 14, 230– 242. 28945989 PMC6613789
  28. [33]Dose J, Huebbe P, Nebel A, Rimbach G (2016) APOE genotype and stress response - a mini review. Lipids Health Dis 15, 121. 27457486 PMC4960866
  29. [35]Belinson H, Kariv-Inbal Z, Kayed R, Masliah E, Michaelson DM (2010) Following activation of the amyloid cascade, apolipoprotein E4 drives the in vivo oligomerization of amyloid-beta resulting in neurodegeneration. J Alzheimers Dis 22, 959– 970. 20858958 PMC5051636
  30. [36]James R, Searcy JL, Le Bihan T, Martin SF, Gliddon CM, Povey J, Deighton RF, Kerr LE, McCulloch J, Horsburgh K (2012) Proteomic analysis of mitochondria in APOE transgenic mice and in response to an ischemic challenge. J Cereb Blood Flow Metab 32, 164– 176. 21878944 PMC3323298
  31. [37]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 (2016) Altered energy metabolism pathways in the posterior cingulate in young adult apolipoprotein E epsilon4 carriers. J Alzheimers Dis 53, 95– 106. 27128370 PMC4942726
  32. [39]Levi O, Jongen-Relo AL, Feldon J, Roses AD, Michaelson DM (2003) ApoE4 impairs hippocampal plasticity isoform-specifically and blocks the environmental stimulation of synaptogenesis and memory. Neurobiol Dis 13, 273– 282. 12901842
  33. [40]Bar R, Boehm-Cagan A, Luz I, Kleper-Wall Y, Michaelson DM (2018) The effects of apolipoprotein E genotype, alpha-synuclein deficiency, and sex on brain synaptic and Alzheimer’s disease-related pathology. Alzheimers Dement (Amst) 10, 1– 11. 29159264 PMC5678739
  34. [41]Belinson H, Michaelson DM (2009) ApoE4-dependent Abeta-mediated neurodegeneration is associated with inflammatory activation in the hippocampus but not the septum. J Neural Transm (Vienna) 116, 1427– 1434. 19370389
  35. [42]Braak H, Braak E (1991) Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathol 1, 213– 216. 1669710
  36. [44]Haas A, Liraz O, Michaelson DM (2012) The effects of apolipoproteins E3 and E4 on the transforming growth factor-beta system in targeted replacement mice. Neurodegener Dis 10, 41– 45. 22301441
  37. [45]Kariv-Inbal Z, Yacobson S, Berkecz R, Peter M, Janaky T, Lutjohann D, Broersen LM, Hartmann T, Michaelson DM (2012) The isoform-specific pathological effects of apoE4 in vivo are prevented by a fish oil (DHA) diet and are modified by cholesterol. J Alzheimers Dis 28, 667– 683. 22057027
  38. [46]Nguyen TN, Padman BS, Lazarou M (2016) Deciphering the molecular signals of PINK1/Parkin mitophagy. Trends Cell Biol 26, 733– 744. 27291334
  39. [47]Bjorkoy G, Lamark T, Pankiv S, Overvatn A, Brech A, Johansen T (2009) Monitoring autophagic degradation of p62/SQSTM1. Methods Enzymol 452, 181– 197. 19200883
  40. [48]Li XC, Hu Y, Wang ZH, Luo Y, Zhang Y, Liu XP, Feng Q, Wang Q, Ye K, Liu GP, Wang JZ (2016) Human wild-type full-length tau accumulation disrupts mitochondrial dynamics and the functions via increasing mitofusins. Sci Rep 6, 24756. 27099072 PMC4838862
  41. [49]Son JM, Sarsour EH, Kakkerla Balaraju A, Fussell J, Kalen AL, Wagner BA, Buettner GR, Goswami PC (2017) Mitofusin 1 and optic atrophy 1 shift metabolism to mitochondrial respiration during aging. Aging Cell 16, 11361145. PMC5595680 28758339
  42. [50]Xu LL, Shen Y, Wang X, Wei LF, Wang P, Yang H, Wang CF, Xie ZH, Bi JZ (2017) Mitochondrial dynamics changes with age in an APPsw/PS1dE9 mouse model of Alzheimer’s disease. Neuroreport 28, 222– 228. 28118288 PMC5321113
  43. [51]Lonskaya I, Hebron ML, Desforges NM, Franjie A, Moussa CE (2013) Tyrosine kinase inhibition increases functional parkin-Beclin-1interaction and enhances amyloid clearance and cognitive performance. EMBO Mol Med 5, 1247– 1262. 23737459 PMC3944464
  44. [52]Salomon-Zimri S, Glat MJ, Barhum Y, Luz I, Boehm-Cagan A, Liraz O, Ben-Zur T, Offen D, Michaelson DM (2016) Reversal of ApoE4-driven brain pathology by vascular endothelial growth factor treatment. J Alzheimers Dis 53, 1443– 1458. 27372644
  45. [53]Woods DC (2017) Mitochondrial heterogeneity: Evaluating mitochondrial subpopulation dynamics in stem cells. Stem Cells Int 2017, 1– 7. PMC5516713 28757879

Cited by

Sorted by citations

Authors
Simonovitch, S., Schmukler, E., Masliah, E., Pinkas-Kramarski, R., & Michaelson, D. M.
Affiliations
  • Tel Aviv University (IL)
  • National Institutes of Health (US)
  • Department of Neurobiology, Sagol School of Neuroscience, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel
Corresponding author
Michaelson, Daniel M.
ORCID
Venue
Journal of Alzheimer's Disease
Publisher
SAGE Publications
Published
2019-08-03
Volume
70
Issue
3
Pages
861-875
ISSN
  • 1387-2877 (ISSN-L)
  • 1875-8908
DOI
10.3233/jad-190074
PMC
PMC7478177
OpenAlex
W2956507615
Cited by
59
References
9
Citations by year
2026: 11 · 2025: 5 · 2024: 14 · 2023: 9 · 2022: 9 · 2021: 6 · 2020: 5
FWCI
1.64
Type
journal article
Language
en
Open access
Locations
  • Journal of Alzheimer s Disease (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (ZIAAG000936)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
APOE ε4, Alzheimer's disease
MeSH terms
PTEN-Induced Putative Kinase, Alzheimer Disease, Animals, Autophagy, Hippocampus, Immunohistochemistry, Neurons, Protein Kinases, Mitochondrial Proteins, Ubiquitin-Protein Ligases, Mice, Apolipoprotein E3, Apolipoprotein E4, Mitochondrial Dynamics, Mitophagy

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