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Cited by 45Autophagy in Disease and TherapyAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

Compromised autophagy and mitophagy in brain ageing and Alzheimer’s diseases.

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Caponio, Domenica, Veverová, Kateřina, Zhang, Shi-qi, Shi, Liu, Wong, Garry, Vyhnalek, Martin, Fang, Evandro F.·2022·Aging Brain
DOI 10.1016/j.nbas.2022.100056PMC PMC9997167
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Abstract

Alzheimer's disease (AD) is one of the most persistent and devastating neurodegenerative disorders of old age, and is characterized clinically by an insidious onset and a gradual, progressive deterioration of cognitive abilities, ranging from loss of memory to impairment of judgement and reasoning. Despite years of research, an effective cure is still not available. Autophagy is the cellular 'garbage' clearance system which plays fundamental roles in neurogenesis, neuronal development and activity, and brain health, including memory and learning. A selective sub-type of autophagy is mitophagy which recognizes and degrades damaged or superfluous mitochondria to maintain a healthy and necessary cellular mitochondrial pool. However, emerging evidence from animal models and human samples suggests an age-dependent reduction of autophagy and mitophagy, which are also compromised in AD. Upregulation of autophagy/mitophagy slows down memory loss and ameliorates clinical features in animal models of AD. In this review, we give an overview of autophagy and mitophagy and their link to the progression of AD. We also summarize approaches to upregulate autophagy/mitophagy. We hypothesize that age-dependent compromised autophagy/mitophagy is a cause of brain ageing and a risk factor for AD, while restoration of autophagy/mitophagy to more youthful levels could return the brain to health.

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  • The anti-aging effects of DRP1 require functional mitophagy, which is typically compromised in the aging brain.

    “the anti-aging effects of DRP1 require functional mitophagy, which is typically compromised in the aging brain (Caponio et al., 2022).”

    From Aging promotes an increase in mitochondrial fragmentation in astrocytes (2024) · cites this paper as Caponio et al., 2022

    The ‘Impaired autophagy and mitophagy in normal ageing brain’ section reports that Drp1 overexpression increased lifespan in flies and that evidence from human post-mortem brains reflects mitophagy dysfunction with ageing. It does not establish that Drp1’s lifespan benefit requires functional mitophagy; the reported Drp1 result is also in flies, not the ageing human brain. (LLM, conf=0.87)

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  1. [1]Dikic I. Elazar Z. Mechanism and medical implications of mammalian autophagy Nat Rev Mol Cell Biol 19 2018 349 364 10.1038/s41580-018-0003-4 29618831 · DOI · Paper page
  2. [4]Ashford T.P. Porter K.R. Cytoplasmic components in hepatic cell lysosomes J Cell Biol 12 1962 198 202 10.1083/jcb.12.1.198 13862833 PMC2106008 · DOI
  3. [5]Klionsky D.J. Autophagy revisited: a conversation with Christian de Duve Autophagy 4 2008 740 743 10.4161/auto.6398 18567941 · DOI
  4. [6]Rubinsztein D.C. Shpilka T. Elazar Z. Mechanisms of autophagosome biogenesis Curr Biol 22 2012 R29 R34 10.1016/j.cub.2011.11.034 22240478 · DOI
  5. [7]Hansen M. Rubinsztein D.C. Walker D.W. Autophagy as a promoter of longevity: insights from model organisms Nat Rev Mol Cell Biol 19 2018 579 593 10.1038/s41580-018-0033-y 30006559 PMC6424591 · DOI · Paper page
  6. [8]Gatica D. Lahiri V. Klionsky D.J. Cargo recognition and degradation by selective autophagy Nat Cell Biol 20 2018 233 242 10.1038/s41556-018-0037-z 29476151 PMC6028034 · DOI · Paper page
  7. [9]Klionsky D.J. Autophagy in major human diseases Embo j 40 2021 e108863 34459017 PMC8488577
  8. [10]Olsvik H.L. FYCO1 Contains a C-terminally Extended, LC3A/B-preferring LC3-interacting region (LIR) motif required for efficient maturation of autophagosomes during basal autophagy J Biol Chem 290 2015 29361 29374 10.1074/jbc.M115.686915 26468287 PMC4705940 · DOI
  9. [11]Sahu R. Microautophagy of cytosolic proteins by late endosomes Dev Cell 20 2011 131 139 10.1016/j.devcel.2010.12.003 21238931 PMC3025279 · DOI · Paper page
  10. [12]Arndt V. Chaperone-assisted selective autophagy is essential for muscle maintenance Curr Biol 20 2010 143 148 10.1016/j.cub.2009.11.022 20060297 · DOI
  11. [13]Kaushik S. Cuervo A.M. The coming of age of chaperone-mediated autophagy Nat Rev Mol Cell Biol 19 2018 365 381 10.1038/s41580-018-0001-6 29626215 PMC6399518 · DOI
  12. [14]Dice J.F. Altered degradation of proteins microinjected into senescent human fibroblasts J Biol Chem 257 1982 14624 14627 7174658
  13. [15]Pfeifer U. Strauss P. Autophagic vacuoles in heart muscle and liver. A comparative morphometric study including circadian variations in meal-fed rats J Mol Cell Cardiol 13 1981 37 49 10.1016/0022-2828(81)90227-3 7253029 · DOI
  14. [16]Kroemer G. Levine B. Autophagic cell death: the story of a misnomer Nat Rev Mol Cell Biol 9 2008 1004 1010 10.1038/nrm2529 18971948 PMC2727358 · DOI · Paper page
  15. [17]Fang E.F. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease Nat Neurosci 22 2019 401 412 10.1038/s41593-018-0332-9 30742114 PMC6693625 · DOI · Paper page
  16. [19]Croteau D.L. Fang E.F. Nilsen H. Bohr V.A. NAD+ in DNA repair and mitochondrial maintenance Cell Cycle 16 2017 491 492 10.1080/15384101.2017.1285631 28145802 PMC5384578 · DOI
  17. [20]Leidal A.M. Levine B. Debnath J. Autophagy and the cell biology of age-related disease Nat Cell Biol 20 2018 1338 1348 10.1038/s41556-018-0235-8 30482941 · DOI · Paper page
  18. [21]Hartl F.U. Protein Misfolding Diseases Annu Rev Biochem 86 2017 21 26 10.1146/annurev-biochem-061516-044518 28441058 · DOI
  19. [22]Lou G. Mitophagy and neuroprotection Trends Mol Med 26 2020 8 20 10.1016/j.molmed.2019.07.002 31375365 · DOI
  20. [23]Kocaturk N.M. Gozuacik D. Crosstalk between mammalian autophagy and the ubiquitin-proteasome system Front Cell Dev Biol 6 2018 128 10.3389/fcell.2018.00128 30333975 PMC6175981 · DOI
  21. [24]Limanaqi F. Promiscuous roles of autophagy and proteasome in neurodegenerative proteinopathies Int J Mol Sci 21 2020 10.3390/ijms21083028 PMC7215558 32344772 · DOI
  22. [25]Hamacher-Brady A. Brady N.R. Gottlieb R.A. Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes J Biol Chem 281 2006 29776 29787 10.1074/jbc.M603783200 16882669 · DOI · Paper page
  23. [26]Kang R. Zeh H.J. Lotze M.T. Tang D. The Beclin 1 network regulates autophagy and apoptosis Cell Death Differ 18 2011 571 580 10.1038/cdd.2010.191 21311563 PMC3131912 · DOI · Paper page
  24. [27]Shibata M. Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1 J Biol Chem 281 2006 14474 14485 10.1074/jbc.M600364200 16522639 · DOI · Paper page
  25. [28]Lipinski M.M. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease Proc Natl Acad Sci U S A 107 2010 14164 14169 10.1073/pnas.1009485107 20660724 PMC2922576 · DOI · Paper page
  26. [29]Fallaize D. Chin L.-S. Li L. Differential submitochondrial localization of PINK1 as a molecular switch for mediating distinct mitochondrial signaling pathways Cell Signal 27 2015 2543 2554 10.1016/j.cellsig.2015.09.020 26436374 PMC4684445 · DOI
  27. [31]Guebel D.V. Torres N.V. Sexual dimorphism and aging in the human hyppocampus: identification, validation, and impact of differentially expressed genes by factorial microarray and network analysis Front Aging Neurosci 8 2016 10.3389/fnagi.2016.00229 PMC5050216 27761111 · DOI
  28. [32]Fang E.F. Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer's disease Nat Neurosci 22 2019 401 412 10.1038/s41593-018-0332-9 30742114 PMC6693625 · DOI · Paper page
  29. [34]Franco-Iborra S. Mutant HTT (huntingtin) impairs mitophagy in a cellular model of Huntington disease Autophagy 17 2021 672 689 10.1080/15548627.2020.1728096 32093570 PMC8032238 · DOI
  30. [35]Evans C.S. Holzbaur E.L.F. Autophagy and mitophagy in ALS Neurobiol Dis 122 2019 35 40 10.1016/j.nbd.2018.07.005 29981842 PMC6366665 · DOI
  31. [36]Kerr J.S. Mitophagy and Alzheimer's disease: cellular and molecular mechanisms Trends Neurosci 40 2017 151 166 10.1016/j.tins.2017.01.002 28190529 PMC5341618 · DOI · Paper page
  32. [39]Glatigny M. Autophagy is required for memory formation and reverses age-related memory decline Curr Biol 29 2019 435 448.e438 10.1016/j.cub.2018.12.021 30661803 · DOI · Paper page
  33. [40]Bjørkøy G. Monitoring autophagic degradation of p62/SQSTM1 Methods Enzymol 452 2009 181 197 10.1016/s0076-6879(08)03612-4 19200883 · DOI
  34. [41]Ott C. Konig J. Hohn A. Jung T. Grune T. Macroautophagy is impaired in old murine brain tissue as well as in senescent human fibroblasts Redox Biol 10 2016 266 273 10.1016/j.redox.2016.10.015 27825071 PMC5099282 · DOI · Paper page
  35. [42]Yu Y. The alteration of autophagy and apoptosis in the hippocampus of rats with natural aging-dependent cognitive deficits Behav Brain Res 334 2017 155 162 10.1016/j.bbr.2017.07.003 28688896 · DOI
  36. [43]De Biase D. Amyloid precursor protein, lipofuscin accumulation and expression of autophagy markers in aged bovine brain BMC Vet Res 13 2017 102 10.1186/s12917-017-1028-1 28407771 PMC5390414 · DOI
  37. [44]Sun N. Measuring in vivo mitophagy Mol Cell 60 2015 685 696 10.1016/j.molcel.2015.10.009 26549682 PMC4656081 · DOI
  38. [45]Bjedov I. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster Cell Metab 11 2010 35 46 10.1016/j.cmet.2009.11.010 20074526 PMC2824086 · DOI · Paper page
  39. [47]Harrison D.E. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice Nature 460 2009 392 395 10.1038/nature08221 19587680 PMC2786175 · DOI · Paper page
  40. [49]Simonsen A. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila Autophagy 4 2008 176 184 10.4161/auto.5269 18059160 · DOI · Paper page
  41. [51]Kuma A. The role of autophagy during the early neonatal starvation period Nature 432 2004 1032 1036 10.1038/nature03029 15525940 · DOI · Paper page
  42. [52]Inoue K. Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway Mol Neurodegener 7 2012 48 10.1186/1750-1326-7-48 22998728 PMC3544596 · DOI · Paper page
  43. [53]Rana A. Rera M. Walker D.W. Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan Proc Natl Acad Sci 110 2013 8638 10.1073/pnas.1216197110 23650379 PMC3666724 · DOI · Paper page
  44. [54]Todd A.M. Staveley B.E. Expression of Pink1 with α-synuclein in the dopaminergic neurons of Drosophila leads to increases in both lifespan and healthspan Genet Mol Res 11 2012 1497 1502 10.4238/2012.May.21.6 22653599 · DOI
  45. [55]Rana A. Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of Drosophila melanogaster Nat Commun 8 2017 448 10.1038/s41467-017-00525-4 28878259 PMC5587646 · DOI · Paper page
  46. [57]Silva M.V.F. Alzheimer’s disease: risk factors and potentially protective measures J Biomed Sci 26 2019 33 10.1186/s12929-019-0524-y 31072403 PMC6507104 · DOI
  47. [59]Selkoe D.J. Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years EMBO Mol Med 8 2016 595 608 10.15252/emmm.201606210 27025652 PMC4888851 · DOI · Paper page
  48. [60]Prillaman M. Alzheimer's drug slows mental decline in trial - but is it a breakthrough? Nature 610 2022 15 16 10.1038/d41586-022-03081-0 36175566 · DOI
  49. [61]Becker R.E. Greig N.H. Giacobini E. Schneider L.S. Ferrucci L. A new roadmap for drug development for Alzheimer's disease Nat Rev Drug Discov 13 2014 156 10.1038/nrd3842-c2 24362362 PMC4668586 · DOI
  50. [62]Sun Y.X. Differential activation of mTOR complex 1 signaling in human brain with mild to severe Alzheimer's disease J Alzheimers Dis 38 2014 437 444 10.3233/jad-131124 23979023 · DOI
  51. [63]Caccamo A. De Pinto V. Messina A. Branca C. Oddo S. Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer's disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature J Neurosci 34 2014 7988 7998 10.1523/jneurosci.0777-14.2014 24899720 PMC4044255 · DOI
  52. [64]Nixon R.A. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study J Neuropathol Exp Neurol 64 2005 113 122 10.1093/jnen/64.2.113 15751225 · DOI · Paper page
  53. [65]Lin W.L. Lewis J. Yen S.H. Hutton M. Dickson D.W. Ultrastructural neuronal pathology in transgenic mice expressing mutant (P301L) human tau J Neurocytol 32 2003 1091 1105 10.1023/b:Neur.0000021904.61387.95 15044841 · DOI
  54. [66]Pickford F. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice J Clin Invest 118 2008 2190 2199 10.1172/jci33585 18497889 PMC2391284 · DOI
  55. [67]Morel E. Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system Nat Commun 4 2013 2250 10.1038/ncomms3250 23907271 PMC3905799 · DOI · Paper page
  56. [68]Yu W.H. Macroautophagy–a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease J Cell Biol 171 2005 87 98 10.1083/jcb.200505082 16203860 PMC2171227 · DOI · Paper page
  57. [70]Nixon R.A. Autophagy, amyloidogenesis and Alzheimer disease J Cell Sci 120 2007 4081 4091 10.1242/jcs.019265 18032783 · DOI · Paper page
  58. [71]Lee S. Sato Y. Nixon R.A. Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer's-like axonal dystrophy J Neurosci 31 2011 7817 7830 10.1523/jneurosci.6412-10.2011 21613495 PMC3351137 · DOI
  59. [72]Fraser PE. et al. Presenilin structure, function and role in Alzheimer disease. Biochim Biophys Acta (BBA) - Mol Basis Dis1502, 1-15, doi:https://doi.org/10.1016/S0925-4439(00)00028-4 (2000). 10899427 · DOI
  60. [73]Cataldo A.M. Presenilin mutations in familial Alzheimer disease and transgenic mouse models accelerate neuronal lysosomal pathology J Neuropathol Exp Neurol 63 2004 821 830 10.1093/jnen/63.8.821 15330337 · DOI
  61. [74]Lee J.H. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations Cell 141 2010 1146 1158 10.1016/j.cell.2010.05.008 20541250 PMC3647462 · DOI · Paper page
  62. [75]Tung Y.-T. Presenilin-1 regulates the expression of p62 to govern p62-dependent tau degradation Mol Neurobiol 49 2014 10 27 10.1007/s12035-013-8482-y 23794287 · DOI
  63. [76]Reddy K. Dysregulation of nutrient sensing and CLEARance in presenilin deficiency Cell Rep 14 2016 2166 2179 10.1016/j.celrep.2016.02.006 26923592 PMC4793148 · DOI
  64. [77]Fedeli C. Filadi R. Rossi A. Mammucari C. Pizzo P. PSEN2 (presenilin 2) mutants linked to familial Alzheimer disease impair autophagy by altering Ca(2+) homeostasis Autophagy 15 2019 2044 2062 10.1080/15548627.2019.1596489 30892128 PMC6844518 · DOI
  65. [80]Sardiello M. A gene network regulating lysosomal biogenesis and function Science 325 2009 473 477 10.1126/science.1174447 19556463 · DOI · Paper page
  66. [81]Wang H. Wang R. Xu S. Lakshmana M.K. Transcription factor EB Is selectively reduced in the nuclear fractions of Alzheimer’s and amyotrophic lateral sclerosis brains Neuroscience Journal 2016 2016 4732837 10.1155/2016/4732837 27433468 PMC4940567 · DOI
  67. [82]Zhang Y.D. Zhao J.J. TFEB participates in the aβ-induced pathogenesis of Alzheimer's disease by regulating the autophagy-lysosome pathway DNA Cell Biol 34 2015 661 668 10.1089/dna.2014.2738 26368054 · DOI
  68. [83]Xiao Q. Neuronal-targeted TFEB accelerates lysosomal degradation of APP, reducing Aβ generation and amyloid plaque pathogenesis J Neurosci 35 2015 12137 12151 10.1523/JNEUROSCI.0705-15.2015 26338325 PMC4556784 · DOI
  69. [84]Song J.-X. A small molecule transcription factor EB activator ameliorates beta-amyloid precursor protein and Tau pathology in Alzheimer's disease models Aging Cell 19 2020 e13069 31858697 PMC6996953
  70. [85]Yamamoto F. TFEB-mediated enhancement of the autophagy-lysosomal pathway dually modulates the process of amyloid β-protein generation in neurons Neuroscience 402 2019 11 22 10.1016/j.neuroscience.2019.01.010 30677488 · DOI
  71. [86]Lauritzen I. Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology Acta Neuropathol 132 2016 257 276 10.1007/s00401-016-1577-6 27138984 PMC4947121 · DOI · Paper page
  72. [87]Lin X.-X. DAF-16/FOXO and HLH-30/TFEB function as combinatorial transcription factors to promote stress resistance and longevity Nat Commun 9 2018 4400 10.1038/s41467-018-06624-0 30353013 PMC6199276 · DOI
  73. [88]Lapierre L.R. The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans Nat Commun 4 2013 2267 10.1038/ncomms3267 23925298 PMC3866206 · DOI
  74. [89]Bao J. Deacetylation of TFEB promotes fibrillar Aβ degradation by upregulating lysosomal biogenesis in microglia Protein Cell 7 2016 417 433 10.1007/s13238-016-0269-2 27209302 PMC4887328 · DOI
  75. [90]Xiao Q. Enhancing astrocytic lysosome biogenesis facilitates Aβ clearance and attenuates amyloid plaque pathogenesis J Neurosci 34 2014 9607 9620 10.1523/JNEUROSCI.3788-13.2014 25031402 PMC4099542 · DOI · Paper page
  76. [91]Polito V.A. Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB EMBO Mol Med 6 2014 1142 1160 10.15252/emmm.201303671 25069841 PMC4197862 · DOI
  77. [92]Wang H, Wang R, Carrera I, Xu S, Lakshmana MK. TFEB Overexpression in the P301S model of tauopathy mitigates increased PHF1 levels and lipofuscin puncta and rescues memory deficits. eNeuro3, ENEURO.0042-0016.2016, doi:10.1523/ENEURO.0042-16.2016 (2016). PMC4876487 27257626 · DOI
  78. [93]Schuur M. Cathepsin D gene and the risk of Alzheimer's disease: a population-based study and meta-analysis Neurobiol Aging 32 2011 1607 1614 10.1016/j.neurobiolaging.2009.10.011 19926167 · DOI
  79. [94]Steinfeld R. Cathepsin D deficiency is associated with a human neurodegenerative disorder Am J Hum Genet 78 2006 988 998 10.1086/504159 16685649 PMC1474096 · DOI
  80. [95]Wu J.W. Neuronal activity enhances tau propagation and tau pathology in vivo Nat Neurosci 19 2016 1085 1092 10.1038/nn.4328 27322420 PMC4961585 · DOI · Paper page
  81. [96]Martini-Stoica H. TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading J Exp Med 215 2018 2355 2377 10.1084/jem.20172158 30108137 PMC6122971 · DOI · Paper page
  82. [97]Medina D.L. Transcriptional activation of lysosomal exocytosis promotes cellular clearance Dev Cell 21 2011 421 430 10.1016/j.devcel.2011.07.016 21889421 PMC3173716 · DOI
  83. [98]Xu Y. TFEB regulates lysosomal exocytosis of tau and its loss of function exacerbates tau pathology and spreading Mol Psychiatry 2020 10.1038/s41380-020-0738-0 PMC7609570 32366951 · DOI
  84. [99]Decressac M. et al. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. Proc Natl Acad Sci U S A110, E1817-1826, doi:10.1073/pnas.1305623110 (2013). PMC3651458 23610405 · DOI · Paper page
  85. [100]Tsunemi T. et al. PGC-1α Rescues Huntington’s disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci Transl Med4, 142ra197-142ra197, doi:10.1126/scitranslmed.3003799 (2012). PMC4096245 22786682 · DOI
  86. [103]Nilsson P. Saido T.C. Dual roles for autophagy: degradation and secretion of Alzheimer's disease Aβ peptide Bioessays 36 2014 570 578 10.1002/bies.201400002 24711225 PMC4316186 · DOI
  87. [104]Vingtdeux V. Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-β peptide degradation Faseb j 25 2011 219 231 10.1096/fj.10-167361 20852062 PMC3005419 · DOI
  88. [105]Schaeffer V. Goedert M. Stimulation of autophagy is neuroprotective in a mouse model of human tauopathy Autophagy 8 2012 1686 1687 10.4161/auto.21488 22874558 PMC3494601 · DOI
  89. [106]Zhao Y. Klotho overexpression improves amyloid-β clearance and cognition in the APP/PS1 mouse model of Alzheimer's disease Aging Cell 19 2020 e13239 32964663 PMC7576297
  90. [109]Jun G. Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes Arch Neurol 67 2010 1473 1484 10.1001/archneurol.2010.201 20697030 PMC3048805 · DOI · Paper page
  91. [110]Ando K. Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer's brains Acta Neuropathol 125 2013 861 878 10.1007/s00401-013-1111-z 23589030 · DOI · Paper page
  92. [111]Moreau K. PICALM modulates autophagy activity and tau accumulation Nat Commun 5 2014 4998 10.1038/ncomms5998 25241929 PMC4199285 · DOI · Paper page
  93. [112]Lee M.J. Lee J.H. Rubinsztein D.C. Tau degradation: The ubiquitin–proteasome system versus the autophagy-lysosome system Prog Neurobiol 105 2013 49 59 10.1016/j.pneurobio.2013.03.001 23528736 · DOI
  94. [113]Ramesh Babu J. Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration J Neurochem 106 2008 107 120 10.1111/j.1471-4159.2008.05340.x 18346206 · DOI · Paper page
  95. [114]Caccamo A. mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies Aging Cell 12 2013 370 380 10.1111/acel.12057 23425014 PMC3655115 · DOI · Paper page
  96. [115]Silva M.C. Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons Nat Commun 11 2020 3258 <http://europepmc.org/abstract/MED/32591533 doi: 10.1038/s41467-020-16984-1 https://europepmc.org/articles/PMC7320012 https://europepmc.org/articles/PMC7320012?pdf=render> 32591533 PMC7320012 · DOI · Paper page
  97. [116]Kim S. NDP52 associates with phosphorylated tau in brains of an Alzheimer disease mouse model Biochem Biophys Res Commun 454 2014 196 201 10.1016/j.bbrc.2014.10.066 25450380 · DOI
  98. [117]Chesser A.S. Ganeshan V. Yang J. Johnson G.V. Epigallocatechin-3-gallate enhances clearance of phosphorylated tau in primary neurons Nutr Neurosci 19 2016 21 31 10.1179/1476830515y.0000000038 26207957 · DOI
  99. [120]Corsetti V. NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of Parkin and UCHL-1: implications in Alzheimer's disease Hum Mol Genet 24 2015 3058 3081 10.1093/hmg/ddv059 25687137 · DOI · Paper page
  100. [121]Pareja-Cajiao M. Age-related impairment of autophagy in cervical motor neurons Exp Gerontol 144 2021 111193 10.1016/j.exger.2020.111193 PMC7968728 33290859 · DOI
  101. [122]Del Prete D. Localization and processing of the amyloid-β protein precursor in mitochondria-associated membranes J Alzheimers Dis 55 2017 1549 1570 10.3233/JAD-160953 27911326 PMC5181669 · DOI
  102. [123]Cenini G. Rüb C. Bruderek M. Voos W. Amyloid β-peptides interfere with mitochondrial preprotein import competence by a coaggregation process Mol Biol Cell 27 2016 3257 3272 10.1091/mbc.E16-05-0313 27630262 PMC5170859 · DOI
  103. [124]Mao P. Mitochondria-targeted catalase reduces abnormal APP processing, amyloid β production and BACE1 in a mouse model of Alzheimer's disease: implications for neuroprotection and lifespan extension Hum Mol Genet 21 2012 2973 2990 10.1093/hmg/dds128 22492996 PMC3373244 · DOI
  104. [125]Manczak M. Kandimalla R. Yin X. Reddy P.H. 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 2018 1332 1342 10.1093/hmg/ddy042 29408999 PMC6455948 · DOI
  105. [126]Reddy P.H. Mutant APP and amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer's disease Hum Mol Genet 27 2018 2502 2516 10.1093/hmg/ddy154 29701781 PMC6031001 · DOI
  106. [127]Wang Z.T. Disrupted-in-schizophrenia-1 protects synaptic plasticity in a transgenic mouse model of Alzheimer's disease as a mitophagy receptor Aging Cell 18 2019 e12860 30488644 PMC6351828
  107. [128]Sorrentino V. Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity Nature 552 2017 187 193 10.1038/nature25143 29211722 PMC5730497 · DOI · Paper page
  108. [129]Ye X. Sun X. Starovoytov V. Cai Q. Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer's disease patient brains Hum Mol Genet 24 2015 2938 2951 10.1093/hmg/ddv056 25678552 PMC4406302 · DOI · Paper page
  109. [130]Martin-Maestro P. Gargini R. Perry G. Avila J. Garcia-Escudero V. PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer's disease Hum Mol Genet 25 2016 792 806 10.1093/hmg/ddv616 26721933 PMC4743695 · DOI
  110. [131]Checler F. Goiran T. Alves da Costa C. Presenilins at the crossroad of a functional interplay between PARK2/PARKIN and PINK1 to control mitophagy: Implication for neurodegenerative diseases Autophagy 13 2017 2004 2005 10.1080/15548627.2017.1363950 28914586 PMC5788489 · DOI
  111. [132]Lazarou M. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy Nature 524 2015 309 314 10.1038/nature14893 26266977 PMC5018156 · DOI · Paper page
  112. [133]Du F. PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer's disease Brain 140 2017 3233 3251 10.1093/brain/awx258 29077793 PMC5841141 · DOI
  113. [134]Cen X. Pharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer’s disease mouse model Nat Commun 11 2020 5731 10.1038/s41467-020-19547-6 33184293 PMC7665171 · DOI
  114. [135]Park J.-S. Kim D.-H. Yoon S.-Y. Regulation of amyloid precursor protein processing by its KFERQ motif BMB Rep 49 2016 337 342 10.5483/bmbrep.2016.49.6.212 26779997 PMC5070722 · DOI
  115. [136]Bourdenx M. Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome Cell 184 2021 2696 2714.e2625 10.1016/j.cell.2021.03.048 33891876 PMC8152331 · DOI · Paper page
  116. [137]Caballero B. Interplay of pathogenic forms of human tau with different autophagic pathways Aging Cell 17 2018 e12692 29024336 PMC5770880
  117. [141]Fernández Á.F. Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice Nature 558 2018 136 140 10.1038/s41586-018-0162-7 29849149 PMC5992097 · DOI · Paper page
  118. [142]Houtman J. Beclin1-driven autophagy modulates the inflammatory response of microglia via NLRP3 EMBO J 38 2019 10.15252/embj.201899430 PMC6376276 30617086 · DOI
  119. [143]Takayama S. Xie Z. Reed J.C. An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators J Biol Chem 274 1999 781 786 10.1074/jbc.274.2.781 9873016 · DOI
  120. [144]Behl C. Breaking BAG: the co-chaperone BAG3 in health and disease Trends Pharmacol Sci 37 2016 672 688 10.1016/j.tips.2016.04.007 27162137 · DOI
  121. [146]Johnston J.A. Ward C.L. Kopito R.R. Aggresomes: a cellular response to misfolded proteins J Cell Biol 143 1998 1883 1898 10.1083/jcb.143.7.1883 9864362 PMC2175217 · DOI · Paper page
  122. [147]Carra S. Brunsting J.F. Lambert H. Landry J. Kampinga H.H. HspB8 participates in protein quality control by a non-chaperone-like mechanism that requires eIF2α phosphorylation* J Biol Chem 284 2009 5523 5532 10.1074/jbc.M807440200 19114712 · DOI
  123. [148]Seidel K. The HSPB8-BAG3 chaperone complex is upregulated in astrocytes in the human brain affected by protein aggregation diseases Neuropathol Appl Neurobiol 38 2012 39 53 10.1111/j.1365-2990.2011.01198.x 21696420 · DOI
  124. [149]Krüger U. Wang Y. Kumar S. Mandelkow E.M. Autophagic degradation of tau in primary neurons and its enhancement by trehalose Neurobiol Aging 33 2012 2291 2305 10.1016/j.neurobiolaging.2011.11.009 22169203 · DOI · Paper page
  125. [150]Elliott E. Tsvetkov P. Ginzburg I. BAG-1 associates with Hsc70.Tau complex and regulates the proteasomal degradation of Tau protein J Biol Chem 282 2007 37276 37284 10.1074/jbc.M706379200 17954934 · DOI
  126. [151]Lei Z. Brizzee C. Johnson G.V.W. BAG3 facilitates the clearance of endogenous tau in primary neurons Neurobiol Aging 36 2015 241 248 10.1016/j.neurobiolaging.2014.08.012 25212465 PMC4268232 · DOI
  127. [152]Fu H. A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology Nat Neurosci 22 2019 47 56 10.1038/s41593-018-0298-7 30559469 PMC6330709 · DOI
  128. [153]Renziehausen J. The cleavage product of amyloid-β protein precursor sAβPPα modulates BAG3-dependent aggresome formation and enhances cellular proteasomal activity J Alzheimers Dis 44 2015 879 896 10.3233/jad-140600 25362034 · DOI
  129. [154]Bagherniya M. Butler A.E. Barreto G.E. Sahebkar A. The effect of fasting or calorie restriction on autophagy induction: A review of the literature Ageing Res Rev 47 2018 183 197 10.1016/j.arr.2018.08.004 30172870 · DOI
  130. [155]Andreotti D.Z. Effects of physical exercise on autophagy and apoptosis in aged brain: human and animal studies Front Nutr 7 2020 10.3389/fnut.2020.00094 PMC7399146 32850930 · DOI
  131. [156]Partridge L. Fuentealba M. Kennedy B.K. The quest to slow ageing through drug discovery Nat Rev Drug Discov 19 2020 513 532 10.1038/s41573-020-0067-7 32467649 · DOI · Paper page
  132. [157]Donati A. et al. Age-related changes in the autophagic proteolysis of rat isolated liver cells: effects of antiaging dietary restrictions. J Gerontol A Biol Sci Med Sci56, B375-383, doi:10.1093/gerona/56.9.b375 (2001). 11524438 · DOI
  133. [158]Pifferi F. et al. Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. Commun Biol1, 30 (2018). <http://europepmc.org/abstract/MED/30271916 https://doi.org/10.1038/s42003-018-0024-8 https://europepmc.org/articles/PMC6123706 https://europepmc.org/articles/PMC6123706?pdf=render>. PMC6123706 30271916 · DOI
  134. [159]Rittig N. Anabolic effects of leucine-rich whey protein, carbohydrate, and soy protein with and without β-hydroxy-β-methylbutyrate (HMB) during fasting-induced catabolism: a human randomized crossover trial Clin Nutr 36 2017 697 705 10.1016/j.clnu.2016.05.004 27265181 · DOI
  135. [160]Vendelbo M.H. Fasting increases human skeletal muscle net phenylalanine release and this is associated with decreased mTOR signaling PLoS One 9 2014 e102031 25020061 PMC4096723
  136. [161]Yang L. Long-term calorie restriction enhances cellular quality-control processes in human skeletal muscle Cell Rep 14 2016 422 428 10.1016/j.celrep.2015.12.042 26774472 · DOI
  137. [162]Pietrocola F. Metabolic effects of fasting on human and mouse blood in vivo Autophagy 13 2017 567 578 10.1080/15548627.2016.1271513 28059587 PMC5361613 · DOI
  138. [163]Escobar K.A. Cole N.H. Mermier C.M. VanDusseldorp T.A. Autophagy and aging: Maintaining the proteome through exercise and caloric restriction Aging Cell 18 2019 e12876 30430746 PMC6351830
  139. [164]Alirezaei M. Short-term fasting induces profound neuronal autophagy Autophagy 6 2010 702 710 10.4161/auto.6.6.12376 20534972 PMC3106288 · DOI
  140. [165]Chen X. Kondo K. Motoki K. Homma H. Okazawa H. Fasting activates macroautophagy in neurons of Alzheimer's disease mouse model but is insufficient to degrade amyloid-beta Sci Rep 5 2015 12115 10.1038/srep12115 26169250 PMC4648430 · DOI
  141. [166]Müller L. Long-term caloric restriction attenuates β-amyloid neuropathology and is accompanied by autophagy in APPswe/PS1delta9 Mice Nutrients 13 2021 985 10.3390/nu13030985 33803798 PMC8003277 · DOI
  142. [167]Kim J. Kundu M. Viollet B. Guan K.-L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 Nat Cell Biol 13 2011 132 141 10.1038/ncb2152 21258367 PMC3987946 · DOI · Paper page
  143. [168]Schwalm C. Activation of autophagy in human skeletal muscle is dependent on exercise intensity and AMPK activation FASEB J 29 2015 3515 3526 10.1096/fj.14-267187 25957282 · DOI
  144. [169]Mejías-Peña Y. et al. Effects of aerobic training on markers of autophagy in the elderly. Age (Dordr)38, 33-33, doi:10.1007/s11357-016-9897-y (2016). PMC5005904 26940016 · DOI · Paper page
  145. [171]Almeida M.F. Effects of mild running on substantia nigra during early neurodegeneration J Sports Sci 36 2018 1363 1370 10.1080/02640414.2017.1378494 28895489 · DOI
  146. [172]Jang Y.C. Association of exercise-induced autophagy upregulation and apoptosis suppression with neuroprotection against pharmacologically induced Parkinson's disease J Exerc Nutrition Biochem 22 2018 1 8 10.20463/jenb.2018.0001 PMC5909076 29673238 · DOI
  147. [173]Zhao N. The effects of treadmill exercise on autophagy in hippocampus of APP/PS1 transgenic mice Neuroreport 29 2018 819 825 10.1097/wnr.0000000000001038 29672446 PMC5999367 · DOI
  148. [174]Bové J. Martínez-Vicente M. Vila M. Fighting neurodegeneration with rapamycin: mechanistic insights Nat Rev Neurosci 12 2011 437 452 10.1038/nrn3068 21772323 · DOI
  149. [175]Miller R.A. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction Aging Cell 13 2014 468 477 10.1111/acel.12194 24341993 PMC4032600 · DOI
  150. [178]Cassano T. Early intrathecal infusion of everolimus restores cognitive function and mood in a murine model of Alzheimer's disease Exp Neurol 311 2019 88 105 10.1016/j.expneurol.2018.09.011 30243986 · DOI
  151. [179]Jiang T. Temsirolimus promotes autophagic clearance of amyloid-β and provides protective effects in cellular and animal models of Alzheimer's disease Pharmacol Res 81 2014 54 63 10.1016/j.phrs.2014.02.008 24602800 · DOI
  152. [180]Jiang T. Temsirolimus attenuates tauopathy in vitro and in vivo by targeting tau hyperphosphorylation and autophagic clearance Neuropharmacology 85 2014 121 130 10.1016/j.neuropharm.2014.05.032 24880087 · DOI
  153. [181]Frederick C. Rapamycin ester analog CCI-779/Temsirolimus alleviates tau pathology and improves motor deficit in mutant tau transgenic mice J Alzheimers Dis 44 2015 1145 1156 10.3233/jad-142097 25408212 · DOI
  154. [182]Rotermund C, Machetanz G, Fitzgerald JC. The therapeutic potential of metformin in neurodegenerative diseases. Front Endocrinol (Lausanne)9, 400-400, doi:10.3389/fendo.2018.00400 (2018). PMC6060268 30072954 · DOI
  155. [183]Anisimov V.N. Metformin: do we finally have an anti-aging drug? Cell Cycle 12 2013 3483 3489 10.4161/cc.26928 24189526 PMC3906334 · DOI
  156. [184]Cabreiro F. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism Cell 153 2013 228 239 10.1016/j.cell.2013.02.035 23540700 PMC3898468 · DOI · Paper page
  157. [187]Kobilo T. AMPK agonist AICAR improves cognition and motor coordination in young and aged mice Learn Mem 21 2014 119 126 10.1101/lm.033332.113 24443745 PMC3895225 · DOI
  158. [188]Andreux P.A. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans Nature Metabolism 1 2019 595 603 10.1038/s42255-019-0073-4 32694802 · DOI · Paper page
  159. [189]Qi Y, Qiu Q, Gu X, Tian Y, Zhang Y. ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts. Sci Rep6, 24700-24700, doi:10.1038/srep24700 (2016). PMC4835770 27089984 · DOI
  160. [190]Fang E.F. Mitophagy and NAD(+) inhibit Alzheimer disease Autophagy 15 2019 1112 1114 10.1080/15548627.2019.1596497 30922179 PMC6526831 · DOI
  161. [191]Xie C. Amelioration of Alzheimer's disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow Nat Biomed Eng 6 2022 76 93 10.1038/s41551-021-00819-5 34992270 PMC8782726 · DOI
  162. [192]Ryu D. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents Nat Med 22 2016 879 888 10.1038/nm.4132 27400265 · DOI · Paper page
  163. [193]Eisenberg T. Cardioprotection and lifespan extension by the natural polyamine spermidine Nat Med 22 2016 1428 1438 10.1038/nm.4222 27841876 PMC5806691 · DOI · Paper page
  164. [195]Yang X. Spermidine inhibits neurodegeneration and delays aging via the PINK1-PDR1-dependent mitophagy pathway in C. elegans Aging 12 2020 16852 16866 10.18632/aging.103578 32902411 PMC7521492 · DOI
  165. [196]Fan J. Spermidine coupled with exercise rescues skeletal muscle atrophy from D-gal-induced aging rats through enhanced autophagy and reduced apoptosis via AMPK-FOXO3a signal pathway Oncotarget 8 2017 17475 17490 10.18632/oncotarget.15728 28407698 PMC5392263 · DOI
  166. [198]Xie C. Aman Y. Frank J. Donate-Lagartos M.J. Gudmundsrud R. Cechova K. Autophagic processes in early- and late-onset Alzheimer’s disease Rothermel B. Diwan A. Autophagy in Health and Disease 2021 Academic Press
  167. [200]Fang E.F. NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome Nat Commun 10 2019 5284 10.1038/s41467-019-13172-8 31754102 PMC6872719 · DOI
  168. [201]Fang E.F. NAD(+) replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair Cell Metab 24 2016 566 581 10.1016/j.cmet.2016.09.004 27732836 PMC5777858 · DOI · Paper page
  169. [202]Fang E.F. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction Cell 157 2014 882 896 10.1016/j.cell.2014.03.026 24813611 PMC4625837 · DOI · Paper page
  170. [203]Fang E.F. A research agenda for ageing in China in the 21st century (2nd edition): Focusing on basic and translational research, long-term care, policy and social networks Ageing Res Rev 64 2020 101174 10.1016/j.arr.2020.101174 PMC7505078 32971255 · DOI
  171. [204]Fang E.F. A research agenda for aging in China in the 21st century Ageing Res Rev 24 2015 197 205 10.1016/j.arr.2015.08.003 26304837 PMC5179143 · DOI
  172. [207]Mattson M.P. Arumugam T.V. Hallmarks of brain aging: adaptive and pathological modification by metabolic states Cell Metab 27 2018 1176 1199 10.1016/j.cmet.2018.05.011 29874566 PMC6039826 · DOI · Paper page
  173. [209]Kingwell K. Turning up mitophagy in Alzheimer disease Nat Rev Drug Discov 2019 10.1038/d41573-019-00035-6 30936509 · DOI
  174. [210]Shintani T. Klionsky D.J. Autophagy in health and disease: a double-edged sword Science 306 2004 990 995 10.1126/science.1099993 15528435 PMC1705980 · DOI
  175. [211]Kobro-Flatmoen A. Re-emphasizing early Alzheimer's disease pathology starting in select entorhinal neurons, with a special focus on mitophagy Ageing Res Rev 67 2021 101307 10.1016/j.arr.2021.101307 33621703 · DOI · Paper page

Cited by

Sorted by citations

Authors
Caponio, D., Veverová, K., Zhang, S.-Q., Shi, L., Wong, G., Vyhnalek, M., & Fang, E. F.
Affiliations
  • University of Oslo (NO)
  • Charles University (CZ)
  • University of Oxford (GB)
  • University of Macau (MO)
Corresponding author
Fang, Evandro F.
ORCID
Venue
Aging Brain
Publisher
Elsevier BV
Published
2022
Volume
2
Pages
100056
ISSN
2589-9589 (ISSN-L)
DOI
10.1016/j.nbas.2022.100056
PMC
PMC9997167
OpenAlex
W4312623056
Cited by
45
References
34
Citations by year
2026: 12 · 2025: 14 · 2024: 14 · 2023: 5
FWCI
1.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Aging Brain (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
Funders
  • Cure Alzheimer's Fund
  • Technology Agency of the Czech Republic (TO01000215)
  • National Natural Science Foundation of China (#81971327, 2020-001, 207819, LX22NPO5107, 262960, TO01000215, 269901, 281931, 2021-021, 262175, 261973)
  • Ministerstvo Školství, Mládeže a Tělovýchovy (LX22NPO5107)
  • China Scholarship Council
  • NordForsk (81971327, 119986)
  • Norges Forskningsråd (269901, 282942, 2021021, #262175, 261973, 281931, TO01000215, 81971327, 2020001, 207819, 262960)
  • Akershus Universitetssykehus (281931, TO01000215, 2020001, 262175, 81971327, #269901, 2021021, 261973, #262960, 207819)
  • NextGenerationEU
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
autophagy, mitophagy, Alzheimer's disease, brain aging, neurodegeneration, mitochondrial quality control, memory loss, age-related decline

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