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Defective Autophagy and Mitophagy in Alzheimer’s Disease: Mechanisms and Translational Implications

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Abstract

The main histopathology of Alzheimer’s disease (AD) is featured by the extracellular accumulation of amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles (NFT) in the brain, which is likely to result from co-pathogenic interactions among multiple factors, e.g., aging or genes. The link between defective autophagy/mitophagy and AD pathologies is still under investigation and not fully established. In this review, we consider how AD is associated with impaired autophagy and mitophagy, and how these impact pathological hallmarks as well as the potential mechanisms. This complicated interplay between autophagy or mitophagy and histopathology in AD suggests that targeting autophagy or mitophagy probably is a promising anti-AD drug candidate. Finally, we review the implications of some new insights for induction of autophagy or mitophagy as the new therapeutic way that targets processes upstream of both NFT and Aβ plaques, and hence stops the neurodegenerative course in AD.

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References

  1. Prince M, Comas-Herrera A, Knapp M, Guerchet M, Karagiannidou M (2016) World Alzheimer Report 2016. In: Improving healthcare for people living with dementia. London, pp 140

  2. Panza F, Lozupone M, Logroscino G, Imbimbo BP (2019) A critical appraisal of amyloid-beta-targeting therapies for Alzheimer disease. Nat Rev Neurol 15(2):73–88

    Article  PubMed  Google Scholar 

  3. Nelson PT, Braak H, Markesbery WR (2009) Neuropathology and cognitive impairment in Alzheimer disease: a complex but coherent relationship. J Neuropathol Exp Neurol 68(1):1–14

    Article  CAS  PubMed  Google Scholar 

  4. Butterfield DA, Halliwell B (2019) Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci 20(3):148–160

    Article  CAS  PubMed  Google Scholar 

  5. Sinha RN (2011) Make dementia a public health priority in India. Indian J Public Health 55(2):67–69

    Article  PubMed  Google Scholar 

  6. As A (2018) 2018 Alzheimer's disease facts and figures. Alzheimers Dement 14(3):367–425

    Article  Google Scholar 

  7. Jagust W (2018) Imaging the evolution and pathophysiology of Alzheimer disease. Nat Rev Neurosci 19(11):687–700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kivipelto M, Mangialasche F, Ngandu T (2018) Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease. Nat Rev Neurol 14(11):653–666

    Article  PubMed  Google Scholar 

  9. Perl DP (2010) Neuropathology of Alzheimer's disease. Mt Sinai J Med 77(1):32–42

    Article  PubMed  PubMed Central  Google Scholar 

  10. Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, Hager K, Andreasen N, Scarpini E, Liu-Seifert H et al (2018) Trial of solanezumab for mild dementia due to Alzheimer's disease. New Engl J Med 378(4):321–330

    Article  CAS  PubMed  Google Scholar 

  11. Egan MF, Kost J, Tariot PN, Aisen PS, Cummings JL, Vellas B, Sur C, Mukai Y, Voss T, Furtek C et al (2018) Randomized Trial of verubecestat for mild-to-moderate Alzheimer's disease. New Engl J Med 378(18):1691–1703

    Article  CAS  PubMed  Google Scholar 

  12. Cummings JL, Cohen S, van Dyck CH, Brody M, Curtis C, Cho W, Ward M, Friesenhahn M, Rabe C, Brunstein F et al (2018) ABBY A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology 90(21):E1889–E1897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun XY, Aisen PS et al (2014) Phase 3 Trials of solanezumab for mild-to-moderate Alzheimer's disease. New Engl J Med 370(4):311–321

    Article  CAS  PubMed  Google Scholar 

  14. Cummings JL, Morstorf T, Zhong K (2014) Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 6(4):37

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mattson MP, Gleichmann M, Cheng A (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60(5):748–766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Moreira PI, Carvalho C, Zhu X, Smith MA, Perry G (2010) Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology. Biochim Biophys Acta 1802(1):2–10

    Article  CAS  PubMed  Google Scholar 

  17. Camandola S, Mattson MP (2017) Brain metabolism in health, aging, and neurodegeneration. EMBO J 36(11):1474–1492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fang EF, Scheibye-Knudsen M, Brace LE, Kassahun H, SenGupta T, Nilsen H, Mitchell JR, Croteau DL, Bohr VA (2014) Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 157(4):882–896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fivenson EM, Lautrup S, Sun N, Scheibye-Knudsen M, Stevnsner T, Nilsen H, Bohr VA, Fang EF (2017) Mitophagy in neurodegeneration and aging. Neurochem Int 109:202–209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fang EF, Kassahun H, Croteau DL, Scheibye-Knudsen M, Marosi K, Lu H, Shamanna RA, Kalyanasundaram S, Bollineni RC, Wilson MA et al (2016) NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab 24(4):566–581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cummins N, Tweedie A, Zuryn S, Bertran-Gonzalez J, Gotz J (2018) Disease-associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria. EMBO J 38(3):e99360

  22. Kerr JS, Adriaanse BA, Greig NH, Mattson MP, Cader MZ, Bohr VA, Fang EF (2017) Mitophagy and Alzheimer's disease: cellular and molecular mechanisms. Trends Neurosci 40(3):151–166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, Lautrup S, Hasan-Olive MM, Caponio D, Dan X et al (2019) Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci 22(3):401–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hurley JH, Young LN (2017) Mechanisms of autophagy initiation. Annu Rev Biochem 86:225–244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Green DR, Galluzzi L, Kroemer G (2011) Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333(6046):1109–1112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147(4):728–741

    Article  CAS  PubMed  Google Scholar 

  27. Sica V, Galluzzi L, Bravo-San Pedro JM, Izzo V, Maiuri MC, Kroemer G (2015) Organelle-specific initiation of autophagy. Mol Cell 59(4):522–539

    Article  CAS  PubMed  Google Scholar 

  28. Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, Kim PK, Lippincott-Schwartz J (2010) Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141(4):656–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13(2):132-U171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, Fullgrabe J, Jackson A, Jimenez Sanchez M, Karabiyik C et al (2017) Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron 93(5):1015–1034

    Article  CAS  PubMed  Google Scholar 

  31. Dooley HC, Razi M, Polson HEJ, Girardin SE, Wilson MI, Tooze SA (2014) WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol Cell 55(2):238–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tsuboyama K, Koyama-Honda I, Sakamaki Y, Koike M, Morishita H, Mizushima N (2016) The ATG conjugation systems are important for degradation of the inner autophagosomal membrane. Science 354(6315):1036–1041

    Article  CAS  PubMed  Google Scholar 

  33. Nishimura T, Kaizuka T, Cadwell K, Sahani MH, Saitoh T, Akira S, Virgin HW, Mizushima N (2013) FIP200 regulates targeting of Atg16L1 to the isolation membrane. Embo Rep 14(3):284–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Itakura E, Kishi-Itakura C, Mizushima N (2012) The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151(6):1256–1269

    Article  CAS  PubMed  Google Scholar 

  35. Frake RA, Ricketts T, Menzies FM, Rubinsztein DC (2015) Autophagy and neurodegeneration. J Clin Invest 125(1):65–74

    Article  PubMed  PubMed Central  Google Scholar 

  36. Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cecconi F, Choi AM, Chu CT, Codogno P, Colombo MI et al (2017) Molecular definitions of autophagy and related processes. EMBO J 36(13):1811–1836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hansen M, Rubinsztein DC, Walker DW (2018) Autophagy as a promoter of longevity: insights from model organisms. Nat Rev Mol Cell Biol 19(9):579–593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nixon RA (2013) The role of autophagy in neurodegenerative disease. Nat Med 19(8):983–997

    Article  CAS  PubMed  Google Scholar 

  39. Vingtdeux V, Chandakkar P, Zhao HT, d’Abramo C, Davies P, Marambaud P (2011) Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-beta peptide degradation. Faseb J 25(1):219–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Barbero-Camps E, Roca-Agujetas V, Bartolessis I, de Dios C, Fernandez-Checa JC, Mari M, Morales A, Hartmann T, Colell A (2018) Cholesterol impairs autophagy-mediated clearance of amyloid beta while promoting its secretion. Autophagy 14(7):1129–1154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Piras A, Collin L, Gruninger F, Graff C, Ronnback A (2016) Autophagic and lysosomal defects in human tauopathies: analysis of post-mortem brain from patients with familial Alzheimer disease, corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol Commun 4:22

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Collin L, Bohrmann B, Gopfert U, Oroszlan-Szovik K, Ozmen L, Gruninger F (2014) Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer's disease. Brain 137(Pt 10):2834–2846

    Article  PubMed  Google Scholar 

  43. Lee JH, McBrayer MK, Wolfe DM, Haslett LJ, Kumar A, Sato Y, Lie PP, Mohan P, Coffey EE, Kompella U et al (2015) Presenilin 1 maintains lysosomal Ca(2+) homeostasis via TRPML1 by regulating vATPase-mediated lysosome acidification. Cell Rep 12(9):1430–1444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Maday S, Holzbaur ELF (2014) Autophagosome biogenesis in primary neurons follows an ordered and spatially regulated pathway. Dev Cell 30(1):71–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tammineni P, Cai Q (2017) Defective retrograde transport impairs autophagic clearance in Alzheimer disease neurons. Autophagy 13(5):982–984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ulland TK, Song WM, Huang SCC, Ulrich JD, Sergushichev A, Beatty WL, Loboda AA, Zhou YY, Caims NJ, Kambal A et al (2017) TREM2 maintains microglial metabolic fitness in Alzheimer's disease. Cell 170(4):649-663.e13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jiang T, Yu JT, Zhu XC, Zhang QQ, Cao L, Wang HF, Tan MS, Gao Q, Qin H, Zhang YD et al (2014) Temsirolimus attenuates tauopathy in vitro and in vivo by targeting tau hyperphosphorylation and autophagic clearance. Neuropharmacology 85:121–130

    Article  CAS  PubMed  Google Scholar 

  48. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM (2005) Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 64(2):113–122

    Article  PubMed  Google Scholar 

  49. Moreau K, Fleming A, Imarisio S, Ramirez AL, Mercer JL, Jimenez-Sanchez M, Bento CF, Puri C, Zavodszky E, Siddiqi F et al (2014) PICALM modulates autophagy activity and tau accumulation. Nat Commun 5:4998

    Article  CAS  PubMed  Google Scholar 

  50. Ando K, Brion JP, Stygelbout V, Suain V, Authelet M, Dedecker R, Chanut A, Lacor P, Lavaur J, Sazdovitch V et al (2013) Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer's brains. Acta Neuropathol 125(6):861–878

    Article  CAS  PubMed  Google Scholar 

  51. Moreau K, Fleming A, Imarisio S, Lopez Ramirez A, Mercer JL, Jimenez-Sanchez M, Bento CF, Puri C, Zavodszky E, Siddiqi F et al (2014) PICALM modulates autophagy activity and tau accumulation. Nat Commun 5:4998

    Article  CAS  PubMed  Google Scholar 

  52. Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A et al (1997) Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med 3(1):67–72

    Article  CAS  PubMed  Google Scholar 

  53. Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Wolfe DM, Martinez-Vicente M, Massey AC, Sovak G et al (2010) Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141(7):1146–1158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Avrahami L, Farfara D, Shaham-Kol M, Vassar R, Frenkel D, Eldar-Finkelman H (2013) Inhibition of glycogen synthase kinase-3 ameliorates beta-amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the Alzheimer disease mouse model: in vivo and in vitro studies. J Biol Chem 288(2):1295–1306

    Article  CAS  PubMed  Google Scholar 

  55. Lee JK, Jin HK, Park MH, Kim BR, Lee PH, Nakauchi H, Carter JE, He X, Schuchman EH, Bae JS (2014) Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer's disease. J Exp Med 211(8):1551–1570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Nilsson P, Loganathan K, Sekiguchi M, Matsuba Y, Hui K, Tsubuki S, Tanaka M, Iwata N, Saito T, Saido TC (2013) Abeta secretion and plaque formation depend on autophagy. Cell Rep 5(1):61–69

    Article  CAS  PubMed  Google Scholar 

  57. Cuyvers E, van der Zee J, Bettens K, Engelborghs S, Vandenbulcke M, Robberecht C, Dillen L, Merlin C, Geerts N, Graff C et al (2015) Genetic variability in SQSTM1 and risk of early-onset Alzheimer dementia: a European early-onset dementia consortium study. Neurobiol Aging 36(5):2005.e15–22

  58. Murphy MP, Hartley RC (2018) Mitochondria as a therapeutic target for common pathologies. Nat Rev Drug Discov 17(12):865–886

    Article  CAS  PubMed  Google Scholar 

  59. Martinez-Vicente M (2017) Neuronal mitophagy in neurodegenerative diseases. Front Mol Neurosci 10:64

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Blanchard V, Moussaoui S, Czech C, Touchet N, Bonici B, Planche M, Canton T, Jedidi I, Gohin M, Wirths O et al (2003) Time sequence of maturation of dystrophic neurites associated with Abeta deposits in APP/PS1 transgenic mice. Exp Neurol 184(1):247–263

    Article  CAS  PubMed  Google Scholar 

  61. Fang EF, Scheibye-Knudsen M, Chua KF, Mattson MP, Croteau DL, Bohr VA (2016) Nuclear DNA damage signalling to mitochondria in aging. Nat Rev Mol Cell Biol 17(5):308–321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Martire S, Mosca L, d’Erme M (2015) PARP-1 involvement in neurodegeneration: a focus on Alzheimer's and Parkinson's diseases. Mech Aging Dev 146–148:53–64

    Article  PubMed  CAS  Google Scholar 

  63. Cai Q, Tammineni P (2016) Alterations in mitochondrial quality control in Alzheimer's disease. Front Cell Neurosci 10:24

    Article  PubMed  PubMed Central  Google Scholar 

  64. Palikaras K, Lionaki E, Tavernarakis N (2018) Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat Cell Biol 20(9):1013–1022

    Article  CAS  PubMed  Google Scholar 

  65. Harper JW, Ordureau A, Heo JM (2018) Building and decoding ubiquitin chains for mitophagy. Nat Rev Mol Cell Biol 19(2):93–108

    Article  CAS  PubMed  Google Scholar 

  66. Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, Caspersen C, Chen X, Pollak S, Chaney M et al (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science 304(5669):448–452

    Article  CAS  PubMed  Google Scholar 

  67. Gwon AR, Park JS, Arumugam TV, Kwon YK, Chan SL, Kim SH, Baik SH, Yang S, Yun YK, Choi Y et al (2012) Oxidative lipid modification of nicastrin enhances amyloidogenic gamma-secretase activity in Alzheimer's disease. Aging Cell 11(4):559–568

    Article  CAS  PubMed  Google Scholar 

  68. Esposito L, Raber J, Kekonius L, Yan F, Yu GQ, Bien-Ly N, Puolivali J, Scearce-Levie K, Masliah E, Mucke L (2006) Reduction in mitochondrial superoxide dismutase modulates Alzheimer's disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice. J Neurosci 26(19):5167–5179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Leuner K, Schutt T, Kurz C, Eckert SH, Schiller C, Occhipinti A, Mai S, Jendrach M, Eckert GP, Kruse SE et al (2012) Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation. Antioxid Redox Signal 16(12):1421–1433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hou Y, Ghosh P, Wan R, Ouyang X, Cheng H, Mattson MP, Cheng A (2014) Permeability transition pore-mediated mitochondrial superoxide flashes mediate an early inhibitory effect of amyloid beta1-42 on neural progenitor cell proliferation. Neurobiol Aging 35(5):975–989

    Article  CAS  PubMed  Google Scholar 

  71. Martin-Maestro P, Gargini R (2017) A AS, Garcia E, Anton LC, Noggle S, Arancio O, Avila J, Garcia-Escudero V: Mitophagy failure in fibroblasts and iPSC-derived neurons of Alzheimer's disease-associated presenilin 1 mutation. Front Mol Neurosci 10:291

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Du H, Guo L, Yan S, Sosunov AA, McKhann GM, Yan SS (2010) Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model. Proc Natl Acad Sci U S A 107(43):18670–18675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Perez MJ, Jara C, Quintanilla RA (2018) Contribution of tau pathology to mitochondrial impairment in neurodegeneration. Front Neurosci 12:441

    Article  PubMed  PubMed Central  Google Scholar 

  74. Dixit R, Ross JL, Goldman YE, Holzbaur EL (2008) Differential regulation of dynein and kinesin motor proteins by tau. Science 319(5866):1086–1089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Vossel KA, Xu JC, Fomenko V, Miyamoto T, Suberbielle E, Knox JA, Ho K, Kim DH, Yu GQ, Mucke L (2015) Tau reduction prevents Abeta-induced axonal transport deficits by blocking activation of GSK3beta. J Cell Biol 209(3):419–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Yin JA, Gao G, Liu XJ, Hao ZQ, Li K, Kang XL, Li H, Shan YH, Hu WL, Li HP et al (2017) Genetic variation in glia-neuron signalling modulates aging rate. Nature 551(7679):198–203

    Article  CAS  PubMed  Google Scholar 

  77. Schulz KL, Eckert A, Rhein V, Mai S, Haase W, Reichert AS, Jendrach M, Muller WE, Leuner K (2012) A new link to mitochondrial impairment in tauopathies. Mol Neurobiol 46(1):205–216

    Article  CAS  PubMed  Google Scholar 

  78. DuBoff B, Gotz J, Feany MB (2012) Tau promotes neurodegeneration via DRP1 mislocalization in vivo. Neuron 75(4):618–632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Li XC, Hu Y, Wang ZH, Luo Y, Zhang Y, Liu XP, Feng Q, Wang Q, Ye K, Liu GP et al (2016) Human wild-type full-length tau accumulation disrupts mitochondrial dynamics and the functions via increasing mitofusins. Sci Rep 6:24756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kopeikina KJ, Carlson GA, Pitstick R, Ludvigson AE, Peters A, Luebke JI, Koffie RM, Frosch MP, Hyman BT, Spires-Jones TL (2011) Tau accumulation causes mitochondrial distribution deficits in neurons in a mouse model of tauopathy and in human Alzheimer's disease brain. Am J Pathol 179(4):2071–2082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Rodriguez-Martin T, Cuchillo-Ibanez I, Noble W, Nyenya F, Anderton BH, Hanger DP (2013) Tau phosphorylation affects its axonal transport and degradation. Neurobiol Aging 34(9):2146–2157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Cieri D, Vicario M, Vallese F, D’Orsi B, Berto P, Grinzato A, Catoni C, De Stefani D, Rizzuto R, Brini M et al (2018) Tau localises within mitochondrial sub-compartments and its caspase cleavage affects ER-mitochondria interactions and cellular Ca(2+) handling. Biochim Biophys Acta Mol Basis Dis 1864(10):3247–3256

    Article  CAS  PubMed  Google Scholar 

  83. Grassi D, Diaz-Perez N, Volpicelli-Daley LA, Lasmezas CI (2019) Palpha-syn* mitotoxicity is linked to MAPK activation and involves tau phosphorylation and aggregation at the mitochondria. Neurobiol Dis 124:248–262

    Article  CAS  PubMed  Google Scholar 

  84. Lin YF, Schulz AM, Pellegrino MW, Lu Y, Shaham S, Haynes CM (2016) Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response. Nature 533(7603):416–419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V (2010) Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS ONE 5(4):e9979

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Johnson SC, Yanos ME, Kayser EB, Quintana A, Sangesland M, Castanza A, Uhde L, Hui J, Wall VZ, Gagnidze A et al (2013) mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 342(6165):1524–1528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kickstein E, Krauss S, Thornhill P, Rutschow D, Zeller R, Sharkey J, Williamson R, Fuchs M, Kohler A, Glossmann H et al (2010) Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc Natl Acad Sci U S A 107(50):21830–21835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Song YM, Lee WK, Lee YH, Kang ES, Cha BS, Lee BW (2016) Metformin restores parkin-mediated mitophagy, suppressed by cytosolic p53. Int J Mol Sci 17(1):122

    Article  PubMed Central  CAS  Google Scholar 

  89. Du J, Liang Y, Xu F, Sun B, Wang Z (2013) Trehalose rescues Alzheimer's disease phenotypes in APP/PS1 transgenic mice. J Pharm Pharmacol 65(12):1753–1756

    Article  CAS  PubMed  Google Scholar 

  90. Li L, Zhang S, Zhang X, Li T, Tang Y, Liu H, Yang W, Le W (2013) Autophagy enhancer carbamazepine alleviates memory deficits and cerebral amyloid-beta pathology in a mouse model of Alzheimer's disease. Curr Alzheimer Res 10(4):433–441

    Article  CAS  PubMed  Google Scholar 

  91. Polito VA, Li H, Martini-Stoica H, Wang B, Yang L, Xu Y, Swartzlander DB, Palmieri M, di Ronza A, Lee VM et al (2014) Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB. EMBO Mol Med 6(9):1142–1160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Song JX, Sun YR, Peluso I, Zeng Y, Yu X, Lu JH, Xu Z, Wang MZ, Liu LF, Huang YY et al (2016) A novel curcumin analog binds to and activates TFEB in vitro and in vivo independent of MTOR inhibition. Autophagy 12(8):1372–1389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Khandelwal PJ, Herman AM, Hoe HS, Rebeck GW, Moussa CE (2011) Parkin mediates beclin-dependent autophagic clearance of defective mitochondria and ubiquitinated Abeta in AD models. Hum Mol Genet 20(11):2091–2102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Muller WE, Eckert GP, Friedland K, Kolesova N, Gaca J, Eckert SH (2018) Mitochondrial pharmacology of dimebon (Latrepirdine) calls for a new look at its possible therapeutic potential in Alzheimer’s disease. Aging Dis 9(4):729–744

    Article  PubMed  PubMed Central  Google Scholar 

  95. Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D, dimebon i (2008) Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet 372(9634):207–215

    Article  CAS  PubMed  Google Scholar 

  96. Lonskaya I, Hebron ML, Desforges NM, Schachter JB, Moussa CE (2014) Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance. J Mol Med (Berl) 92(4):373–386

    Article  CAS  Google Scholar 

  97. Lonskaya I, Hebron ML, Desforges NM, Franjie A, Moussa CE (2013) Tyrosine kinase inhibition increases functional parkin-Beclin-1 interaction and enhances amyloid clearance and cognitive performance. EMBO Mol Med 5(8):1247–1262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Luchsinger JA, Perez T, Chang H, Mehta P, Steffener J, Pradabhan G, Ichise M, Manly J, Devanand DP, Bagiella E (2016) Metformin in amnestic mild cognitive impairment: results of a pilot randomized placebo controlled clinical trial. J Alzheimers Dis 51(2):501–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Liu D, Pitta M, Jiang H, Lee JH, Zhang G, Chen X, Kawamoto EM, Mattson MP (2013) Nicotinamide forestalls pathology and cognitive decline in Alzheimer mice: evidence for improved neuronal bioenergetics and autophagy procession. Neurobiol Aging 34(6):1564–1580

    Article  CAS  PubMed  Google Scholar 

  100. Turunc Bayrakdar E, Uyanikgil Y, Kanit L, Koylu E, Yalcin A (2014) Nicotinamide treatment reduces the levels of oxidative stress, apoptosis, and PARP-1 activity in Abeta(1–42)-induced rat model of Alzheimer's disease. Free Radic Res 48(2):146–158

    Article  CAS  PubMed  Google Scholar 

  101. Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, Harger A, Schipke J, Zimmermann A, Schmidt A et al (2016) Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med 22(12):1428–1438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. McManus MJ, Murphy MP, Franklin JL (2011) The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer's disease. J Neurosci 31(44):15703–15715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Geisler JG, Marosi K, Halpern J, Mattson MP (2017) DNP, mitochondrial uncoupling, and neuroprotection: a little dab'll do ya. Alzheimers Dement 13(5):582–591

    Article  PubMed  Google Scholar 

  104. Reddy PH, Manczak M, Kandimalla R (2017) Mitochondria-targeted small molecule SS31: a potential candidate for the treatment of Alzheimer's disease. Hum Mol Genet 26(8):1483–1496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Sorrentino V, Romani M, Mouchiroud L, Beck JS, Zhang H, D’Amico D, Moullan N, Potenza F, Schmid AW, Rietsch S et al (2017) Enhancing mitochondrial proteostasis reduces amyloid-beta proteotoxicity. Nature 552(7684):187–193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Yao J, Chen S, Mao Z, Cadenas E, Brinton RD (2011) 2-Deoxy-D-glucose treatment induces ketogenesis, sustains mitochondrial function, and reduces pathology in female mouse model of Alzheimer's disease. PLoS ONE 6(7):e21788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Fonseca I, Gordino G, Moreira S, Nunes MJ, Azevedo C, Gama MJ, Rodrigues E, Rodrigues CMP, Castro-Caldas M (2017) Tauroursodeoxycholic acid protects against mitochondrial dysfunction and cell death via mitophagy in human neuroblastoma cells. Mol Neurobiol 54(8):6107–6119

    Article  CAS  PubMed  Google Scholar 

  108. Eckert SH, Gaca J, Kolesova N, Friedland K, Eckert GP, Muller WE (2018) Mitochondrial pharmacology of dimebon (Latrepirdine) calls for a new look at its possible therapeutic potential in Alzheimer's disease. Aging Dis 9(4):729–744

    Article  PubMed  PubMed Central  Google Scholar 

  109. Shi WY, Xiao D, Wang L, Dong LH, Yan ZX, Shen ZX, Chen SJ, Chen Y, Zhao WL (2012) Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy. Cell Death Dis 3:e275

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. East DA, Fagiani F, Crosby J, Georgakopoulos ND, Bertrand H, Schaap M, Fowkes A, Wells G, Campanella M (2014) PMI: a DeltaPsim independent pharmacological regulator of mitophagy. Chem Biol 21(11):1585–1596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Mattson MP, Arumugam TV (2018) Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metab 27(6):1176–1199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

The study was supported by the Projects of National Science Foundation of China (No. 81600977) and the Projects of Wenzhou city Committee of Science and Technology (Y20170067 and Y20180137 and Y2020427) and the Projects of Natural Science Foundation of Zhejiang Province (Y19H090059).

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Author notes

  1. Jie Chen and Hai-Jun He contributed equally to this work

Authors and Affiliations

  1. Department of Rehabilitation Medicine, Ningbo Medical Center Li Huili Hospital, Ningbo, 315000, China

    Jie Chen

  2. Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China

    Hai-Jun He, Qianqian Ye, Feifei Feng & Chenglong Xie

  3. NHC Key Laboratory of Family Planning and Healthy, Hebei Key Laboratory of Reproductive Medicine, Hebei Research Institute for Family Planning Science and Technology, Shijiazhuang, 050071, Hebei, China

    Ruiyu Han

  4. The Center of Traditional Chinese Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325027, China

    Wen-Wen Wang

  5. Department of Psychiatry, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China

    Yingying Gu

  6. Institute of Aging, Wenzhou Medical University, Wenzhou, Zhejiang, China

    Chenglong Xie

  7. Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Wenzhou, China

    Chenglong Xie

Authors
  1. Jie Chen
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  2. Hai-Jun He
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Contributions

WWW carried out the idea and searched relevant literatures; HJH and YYG made substantial contributions to conception and design and figures/tables. JC revised the manuscript. RYH and CLX were involved in drafting the manuscript and supervised the process. All the authors read and approved the final manuscript.

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Correspondence to Ruiyu Han or Chenglong Xie.

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Key Points

1. Update the interplay between autophagy or mitophagy and histopathology in AD.

2. Interventional strategies of targeting autophagy or mitophagy as promising anti-AD drug candidates.

3. Induction of autophagy or mitophagy as the new therapeutic strategy that targets processes upstream of both Aβ and tau, and therefore forestalls the neurodegenerative process in AD.

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Chen, J., He, HJ., Ye, Q. et al. Defective Autophagy and Mitophagy in Alzheimer’s Disease: Mechanisms and Translational Implications. Mol Neurobiol 58, 5289–5302 (2021). https://doi.org/10.1007/s12035-021-02487-7

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  • DOI: https://doi.org/10.1007/s12035-021-02487-7

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