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Mitochondrial Dysfunction in Alzheimer’s Disease and Progress in Mitochondria-Targeted Therapeutics

  • Geropsychiatry & Cognitive Disorders of Late Life (P Newhouse, Section Editor)
  • Published:
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Abstract

Purpose of Review

Mitochondria are essential for facilitating energy homeostasis under ever-changing environmental conditions. Mitochondrial dysfunction has been suggested to either play a primary role in the development of multiple human diseases and/or significantly contribute to disease progression. Here, we review recent findings on mitochondrial dysfunction in Alzheimer’s disease (AD) and strategies for the development of mitochondria-targeted therapies.

Recent Findings

Multiple mechanisms essential for proper mitochondrial functioning including biogenesis and turnover, fission/fusion, trafficking, and bioenergetics are affected in AD. Few therapeutic strategies were developed to address these problems.

Summary

While a conclusive statement on the causative role of mitochondrial dysfunction in AD remains elusive, the available evidence suggests that improving mitochondrial function via pharmacological and/or non-pharmacological interventions could delay the onset and slow the progression of AD. Further research and outcomes of ongoing clinical trials should extend our understanding and help to validate conclusions regarding causation.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. •• Murphy MP, Hartley RC. Mitochondria as a therapeutic target for common pathologies. Nat Rev Drug Discov. 2018;17(12):865–86 Excellent review on current mitochondrial therapeutics and pathways associated with various pathologies.

    Article  CAS  PubMed  Google Scholar 

  2. Shaughnessy DT, McAllister K, Worth L, Haugen AC, Meyer JN, Domann FE, et al. Mitochondria, energetics, epigenetics, and cellular responses to stress. Environ Health Perspect. 2014;122(12):1271–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Quijano C, Trujillo M, Castro L, Trostchansky A. Interplay between oxidant species and energy metabolism. Redox Biol. 2016;8:28–42.

    Article  CAS  PubMed  Google Scholar 

  4. Picard M. Mitochondrial synapses: intracellular communication and signal integration. Trends Neurosci. 2015;38(8):468–74.

    Article  CAS  PubMed  Google Scholar 

  5. Melber A, Haynes CM. UPRmt regulation and output: a stress response mediated by mitochondrial-nuclear communication. Cell Res. 2018;28(3):281–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hill S, Sataranatarajan K, Remmen HV. Role of signaling molecules in mitochondrial stress response. Front Genet. 2018;9:225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ristow M, Schmeisser K. Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS). Dose Response. 2014;12(2):288–341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bárcena C, Mayoral P, Quirós PM. Mitohormesis, an antiaging paradigm. Int Rev Cell Mol Biol. 2018;340:35–77.

    Article  PubMed  Google Scholar 

  9. Chen H, Chan DC. Mitochondrial dynamics--fusion, fission, movement, and mitophagy—in neurodegenerative diseases. Hum Mol Genet. 2009;18(R2):R169–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Saxton WM, Hollenbeck PJ. The axonal transport of mitochondria. J Cell Sci. 2012;125(9):2095–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. https://www.alz.org/alzheimers-dementia/facts-figures. This is Alzheimer's Disease Facts and Figures report published by the Alzheimer’s Association.

  12. Talwar P, Sinha J, Grover S, Rawat C, Kushwaha S, Agarwal R, et al. Dissecting complex and multifactorial nature of Alzheimer’s disease pathogenesis: a clinical, genomic, and systems biology perspective. Mol Neurobiol. 2016;53(7):4833–64.

    Article  CAS  PubMed  Google Scholar 

  13. Deming Y, Dumitrescu L, Barnes LL, Thambisetty M, Kunkle B, Gifford KA, et al. Sex-specific genetic predictors of Alzheimer’s disease biomarkers. Acta Neuropathol. 2018;136(6):857–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. •• Swerdlow RH. Mitochondria and mitochondrial cascades in Alzheimer's disease. J Alzheimers Dis. 2018;62(3):1403–16 Current review of evidence for the mitochondrial cascade hypothesis in AD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. de la Monte SM. Type 3 diabetes is sporadic Alzheimer’s disease: mini-review. Eur Neuropsychopharmacol. 2014;24(12):1954–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Caselli RJ, Chen K, Lee W, Alexander GE, Reiman EM. Correlating cerebral hypometabolism with future memory decline in subsequent converters to amnestic pre-mild cognitive impairment. Arch Neurol. 2008;65(9):1231–6.

    Article  PubMed  Google Scholar 

  17. Langbaum JBS, Chen K, Caselli RJ, Lee W, Reschke C, Bandy D, et al. Hypometabolism in Alzheimer-affected brain regions in cognitively healthy Latino individuals carrying the apolipoprotein E epsilon 4 allele. Arch Neurol. 2010;67(4):462–8.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Mosconi L. Brain glucose metabolism in the early and specific diagnosis of Alzheimer’s disease—FDG-PET studies in MCI and AD. Eur J Nucl Med Mol Imaging. 2005;32(4):486–510.

    Article  CAS  PubMed  Google Scholar 

  19. Mosconi L, Pupi A, De Leon MJ. Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann N Y Acad Sci. 2008;1147:180–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Silverman DHS, Small GW, Chang CY, Lu CS, de Aburto MAK, Chen W, et al. Positron emission tomography in evaluation of dementia—regional brain metabolism and long-term outcome. JAMA. 2001;286(17):2120–7.

    Article  CAS  PubMed  Google Scholar 

  21. Iborra FJ, Kimura H, Cook PR. The functional organization of mitochondrial genomes in human cells. BMC Biol. 2004;2:9–18.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Wiesner RJ, Ruegg JC, Morano I. Counting target molecules by exponential polymerase chain-reaction - copy number of mitochondrial-DNA in rat-tissues. Biochem Biophys Res Commun. 1992;183(2):553–9.

    Article  CAS  PubMed  Google Scholar 

  23. • Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45(12):1452–8 Meta analysis of genetic loci associated with AD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Swerdlow RH. Mitochondria and cell bioenergetics: increasingly recognized components and a possible etiologic cause of Alzheimer’s disease. Antioxid Redox Signal. 2012;16(12):1434–U163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lee WT, Sun X, Tsai TS, Johnson JL, Gould JA, Garama DJ, et al. Mitochondrial DNA haplotypes induce differential patterns of DNA methylation that result in differential chromosomal gene expression patterns. Cell Death Discov. 2017;3:17062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. • Ridge PG, Kauwe JSK. Mitochondria and Alzheimer’s disease: the role of mitochondrial genetic variation. Curr Genet Med Rep. 2018;6(1):1–10 Review on mtDNA polymorphisms and haplogroups in AD.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Phillips NR, Simpkins JW, Roby RK. Mitochondrial DNA deletions in Alzheimer’s brains: a review. Alzheimer’s Dementia. 2014;10(3):393–400.

    Article  PubMed  Google Scholar 

  28. Coskun PE, Beal MF, Wallace DC. Alzheimer’s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci U S A. 2004;101(29):10726–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hamblet NS, Ragland B, Ali M, Conyers B, Castora FJ. Mutations in mitochondrial-encoded cytochrome c oxidase subunits I, II, and III genes detected in Alzheimer’s disease using single-strand conformation polymorphism. Electrophoresis. 2006;27(2):398–408.

    Article  CAS  PubMed  Google Scholar 

  30. van der Walt JM, Dementieva YA, Martin ER, Scott WK, Nicodemus KK, Kroner CC, et al. Analysis of European mitochondrial haplogroups with Alzheimer disease risk. Neurosci Lett. 2004;365(1):28–32.

    Article  CAS  PubMed  Google Scholar 

  31. Carrieri G, Bonafe M, De Luca M, Rose G, Varcasia O, Bruni A, et al. Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer’s disease. Hum Genet. 2001;108(3):194–8.

    Article  CAS  PubMed  Google Scholar 

  32. Ridge PG, Koop A, Maxwell TJ, Bailey MH, Swerdlow RH, Kauwe JS, et al. Mitochondrial haplotypes associated with biomarkers for Alzheimer’s disease. PLoS One. 2013;8(9):e74158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Moreira PI, Carvalho C, Zhu X, Smith MA, Perry G. Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. BBA Mol Basis Dis. 1802;2009:2–10.

    Google Scholar 

  34. Wang XL, Wang WZ, Li L, Perry G, Lee HG, Zhu XW. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta – Mol Basis Dis. 2014;1842(8):1240–7.

    Article  CAS  Google Scholar 

  35. Bosetti F, Brizzi F, Barogi S, Mancuso M, Siciliano G, Tendi EA, et al. Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer's disease. Neurobiol Aging. 2002;23(3):371–6.

    Article  CAS  PubMed  Google Scholar 

  36. Valla J, Berndt JD, Gonzalez-Lima F. Energy hypometabolism in posterior cingulate cortex of Alzheimer’s patients: superficial laminar cytochrome oxidase associated with disease duration. J Neurosci. 2001;21(13):4923–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kish SJ, Bergeron C, Rajput A, Dozic S, Mastrogiacomo F, Chang LJ, et al. Brain cytochrome-oxidase in Alzheimer’s disease. J Neurochem. 1992;59(2):776–9.

    Article  CAS  PubMed  Google Scholar 

  38. Mutisya EM, Bowling AC, Beal MF. Cortical cytochrome-oxidase activity is reduced in Alzheimer’s disease. J Neurochem. 1994;63(6):2179–84.

    Article  CAS  PubMed  Google Scholar 

  39. Maurer I, Zierz S, Moller HJ. A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiol Aging. 2000;21(3):455–62.

    Article  CAS  PubMed  Google Scholar 

  40. Kawamata H, Manfredi G. Proteinopathies and OXPHOS dysfunction in neurodegenerative diseases. J Cell Biol. 2017;216:3917–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. •• Cheng Y, Bai F. The association of tau with mitochondrial dysfunction in Alzheimer’s disease. Front Neurosci. 2018;12:163 Comprehensive overview of Tau protein and its contribution to AD.

    Article  PubMed  PubMed Central  Google Scholar 

  42. David DC, Hauptmann S, Scherping I, Schuessel K, Keil U, Rizzu P, et al. Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J Biol Chem. 2005;280(25):23802–14.

    Article  CAS  PubMed  Google Scholar 

  43. Rhein V, Song X, Wiesner A, Ittner LM, Baysang G, Meier F, et al. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci U S A. 2009;106(47):20057–62.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Chowdhury SR, Djordjevic J, Albensi BC, Fernyhough P. Simultaneous evaluation of substrate-dependent oxygen consumption rates and mitochondrial membrane potential by TMRM and safranin in cortical mitochondria. Biosci Rep. 2016;36:3315.

    Article  CAS  Google Scholar 

  45. Walls KC, Coskun P, Gallegos-Perez JL, Zadourian N, Freude K, Rasool S, et al. Swedish Alzheimer mutation induces mitochondrial dysfunction mediated by HSP60 mislocalization of amyloid precursor protein (APP) and beta-amyloid. J Biol Chem. 2012;287(36):30317–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Martino Adami PV, Quijano C, Magnani N, Galeano P, Evelson P, Cassina A, et al. Synaptosomal bioenergetic defects are associated with cognitive impairment in a transgenic rat model of early Alzheimer’s disease. J Cereb Blood Flow Metab. 2017;37(1):69–84.

    Article  PubMed  Google Scholar 

  47. Sonntag K-C, Ryu W-I, Amirault KM, Healy RA, Siegel AJ, McPhie DL, et al. Late-onset Alzheimer’s disease is associated with inherent changes in bioenergetics profiles. Sci Rep. 2017;7:14038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Silva DF, Selfridge JE, Lu J, Lezi E, Roy N, Hutfles L, et al. Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines. Hum Mol Genet. 2013;22:3931–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Parker WD, Filley CM, Parks JK. Cytochrome-oxidase deficiency in Alzheimer’s disease. Neurology. 1990;40(8):1302–3.

    Article  PubMed  Google Scholar 

  50. Sims NR, Finegan JM, Blass JP. Altered glucose-metabolism in fibroblasts from patients with Alzheimer’s disease. N Engl J Med. 1985;313(10):638–9.

    Article  CAS  PubMed  Google Scholar 

  51. Perez MJ, Ponce DP, Osorio-Fuentealba C, Behrens MI, Quintanilla RA. Mitochondrial bioenergetics is altered in fibroblasts from patients with sporadic Alzheimer’s disease. Front Neurosci. 2017;11:553.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Mastroeni D, Khdour OM, Delvaux E, Nolz J, Olsen G, Berchtold N, et al. Nuclear but not mitochondrial-encoded oxidative phosphorylation genes are altered in aging, mild cognitive impairment, and Alzheimer’s disease. Alzheimer's Dementia. 2017;13:510–9.

    Article  PubMed  Google Scholar 

  53. Lunnon K, Keohane A, Pidsley R, Newhouse S, Riddoch-Contreras J, Thubron EB, et al. Mitochondrial genes are altered in blood early in Alzheimer’s disease. Neurobiol Aging. 2017;53:36–47.

    Article  CAS  PubMed  Google Scholar 

  54. Chandrasekaran K, Hatanpaa K, Rapoport SI, Brady DR. Decreased expression of nuclear and mitochondrial DNA-encoded genes of oxidative phosphorylation in association neocortex in Alzheimer disease. Mol Brain Res. 1997;44(1):99–104.

    Article  CAS  PubMed  Google Scholar 

  55. Kenney PM. Alzheimer’s disease frontal cortex mitochondria show a loss of individual respiratory proteins but preservation of respiratory complexes. In: Bennett J, editor.: Neurodegeneration Therapeutics; 2019.

  56. Sies H, Berndt C, Jones DP. Oxidative stress. Annu Rev Biochem. 2017;86:715–48.

    Article  CAS  PubMed  Google Scholar 

  57. Tonnies E, Trushina E. Oxidative stress, synaptic dysfunction, and Alzheimer’s disease. J Alzheimers Dis. 2017;57(4):1105–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med. 1991;11(1):81–128.

    Article  CAS  PubMed  Google Scholar 

  59. Hensley K, Hall N, Subramaniam R, Cole P, Harris M, Aksenov M, et al. Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. J Neurochem. 1995;65(5):2146–56.

    Article  CAS  PubMed  Google Scholar 

  60. Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci. 2014;39(4):199–218.

    Article  CAS  PubMed  Google Scholar 

  61. Wojsiat J, Zoltowska KM, Laskowska-Kaszub K, Wojda U. Oxidant/antioxidant imbalance in Alzheimer’s disease: therapeutic and diagnostic prospects. Oxid Med Cell Longev. 2018;2018:6435861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Persson T, Popescu BO, Cedazo-Minguez A. Oxidative stress in Alzheimer’s disease: why did antioxidant therapy fail? Oxidative Med Cell Longev. 2014;2014:427318.

    Article  CAS  Google Scholar 

  63. Mathers J, Fraser JA, McMahon M, Saunders RD, Hayes JD, McLellan LI. Antioxidant and cytoprotective responses to redox stress. Biochem Soc Symp. 2004;71:157–76.

    Article  CAS  Google Scholar 

  64. Mattson MP. Hormesis defined. Ageing Res Rev. 2008;7(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  65. • Ristow M. Unraveling the truth about antioxidants: mitohormesis explains ROS-induced health benefits. Nat Med. 2014;20(7):709–11 Review detailing mitohormesis and the involvement of ROS as a signalling molecule.

    Article  CAS  PubMed  Google Scholar 

  66. Schmeisser S, Priebe S, Groth M, Monajembashi S, Hemmerich P, Guthke R, et al. Neuronal ROS signaling rather than AMPK/sirtuin-mediated energy sensing links dietary restriction to lifespan extension. Mol Metab. 2013;2(2):92–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Merry TL, Ristow M. Mitohormesis in exercise training. Free Radic Biol Med. 2016;98:123–30.

    Article  CAS  PubMed  Google Scholar 

  68. Di Meo S, Reed TT, Venditti P, Victor VM. Role of ROS and RNS sources in physiological and pathological conditions. Oxidative Med Cell Longev. 2016;2016:1245049.

    Google Scholar 

  69. Cagalinec M, Safiulina D, Liiv M, Liiv J, Choubey V, Wareski P, et al. Principles of the mitochondrial fusion and fission cycle in neurons. J Cell Sci. 2013;126(10):2187–97.

    Article  CAS  PubMed  Google Scholar 

  70. Cipolat S, de Brito OM, Dal Zilio B, Scorrano L. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A. 2004;101(45):15927–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Song ZY, Ghochani M, McCaffery JM, Frey TG, Chan DC. Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion. Mol Biol Cell. 2009;20(15):3525–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Reddy PH, Reddy TP, Manczak M, Calkins MJ, Shirendeb U, Mao PZ. Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases. Brain Res Rev. 2011;67(1–2):103–18.

    Article  CAS  PubMed  Google Scholar 

  73. Anand R, Wai T, Baker MJ, Kladt N, Schauss AC, Rugarli E, et al. The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. J Cell Biol. 2014;204(6):919–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ramos ES, Larsson NG, Mourier A. Bioenergetic roles of mitochondrial fusion. Biochim Biophys Acta Bioenergetics. 2016;1857(8):1277–83.

    Article  CAS  Google Scholar 

  75. Onyango IG, Lu J, Rodova M, Lezi E, Crafter AB, Swerdlow RH. Regulation of neuron mitochondrial biogenesis and relevance to brain health. Biochim Biophys Acta. 2010;1802(1):228–34.

    Article  CAS  PubMed  Google Scholar 

  76. • Onyango IG, Dennis J, Khan SM. Mitochondrial dysfunction in Alzheimer’s disease and the rationale for bioenergetics based therapies. Aging Dis. 2016;7:201–14 Excellent review detailing mitochondria-targeted therapeutics and mechanisms.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Yu SB, Pekkurnaz G. Mechanisms orchestrating mitochondrial dynamics for energy homeostasis. J Mol Biol. 2018;403:3922–41.

    Article  CAS  Google Scholar 

  78. Trushina E, Nemutlu E, Zhang S, Christensen T, Camp J, Mesa J, et al. Defects in mitochondrial dynamics and metabolomic signatures of evolving energetic stress in mouse models of familial Alzheimer’s disease. PLoS One. 2012;7:e32737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Manczak M, Calkins MJ, Reddy PH. 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. 2011;20(13):2495–509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, et al. Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci U S A. 2008;105(49):19318–23.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Wang X, Su B, Fujioka H, Zhu X. Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer’s disease patients. Am J Pathol. 2008;173(2):470–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wang X, Su B, Lee H-G, Li X, Perry G, Smith MA, et al. Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci. 2009;29:9090–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wang S, Song J, Tan M, Albers KM, Jia J. Mitochondrial fission proteins in peripheral blood lymphocytes are potential biomarkers for Alzheimer’s disease. Europ J Neurol. 2012;19(7):1015–22.

    Article  CAS  Google Scholar 

  84. Bonda DJ, Wang XL, Perry G, Smith MA, Zhu XW. Mitochondrial dynamics in Alzheimer’s disease opportunities for future treatment strategies. Drugs Aging. 2010;27(3):181–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. • Manczak M, Sesaki H, Kageyama Y, Reddy PH. Dynamin-related protein 1 heterozygote knockout mice do not have synaptic and mitochondrial deficiencies. Biochim Biophys Acta. 2012;1822(6):862–74 Studies investigating the role of mitochondria dynamic fission regulator DRP1 in promoting Aβ and Tau pathogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. • Manczak M, Reddy PH. Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimers disease neurons: implications for mitochondrial dysfunction and neuronal damage. Hum Mol Genet. 2012;21(11):2538 Studies investigating the role of mitochondria dynamic fission regulator DRP1 in promoting Aβ and Tau pathogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Calkins MJ, Manczak M, Mao P, Shirendeb U, Reddy PH. Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer;s disease. Hum Mol Genet. 2011;20(23):4515–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. •• Reddy PH. Inhibitors of mitochondrial fission as a therapeutic strategy for diseases with oxidative stress and mitochondrial dysfunction. J Alzheimers Dis. 2014;40(2):245–56 Review describing the benefit of targeting mitochondrial dynamic regulators in AD.

    Article  PubMed  PubMed Central  Google Scholar 

  89. • Zhang L, Trushin S, Christensen TA, Bachmeier BV, Gateno B, Schroeder A, et al. Altered brain energetics induces mitochondrial fission arrest in Alzheimer’s disease. Sci Rep. 2016;6:18725 Study describing the appearance of a new mitochondrial phenotype, MOAS or mitochondrial nanotunnels in AD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Tyumentsev MA, Stefanova NA, Kiseleva EV, Kolosova NG. Mitochondria with morphology characteristic for Alzheimer’s disease patients are found in the brain of OXYS rats. Biochemistry-Moscow. 2018;83(9):1083–8.

    Article  CAS  PubMed  Google Scholar 

  91. Morozov YM, Datta D, Paspalas CD, Arnsten AFT. Ultrastructural evidence for impaired mitochondrial fission in the aged rhesus monkey dorsolateral prefrontal cortex. Neurobiol Aging. 2017;51:9–18.

    Article  CAS  PubMed  Google Scholar 

  92. • Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science. 2005;307(5713):1282–8 Impaired mitochondrial transport described as one of the key early events in AD.

    Article  CAS  PubMed  Google Scholar 

  93. Trimmer PA, Borland MK. Differentiated Alzheimer’s disease transmitochondrial cybrid cell lines exhibit reduced organelle movement. Antioxid Redox Signal. 2005;7(9–10):1101–9.

    Article  CAS  PubMed  Google Scholar 

  94. Cai Q, Tammineni P. Alterations in mitochondrial quality control in Alzheimer’s disease. Front Cell Neurosci. 2016;10:24.

    PubMed  PubMed Central  Google Scholar 

  95. • Zhang L, Trushin S, Christensen TA, Tripathi U, Hong C, Geroux RE, et al. Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane. Neurobiol Dis. 2018;114:1–16 Investigating the toxicity of Aβ aggregation on mitochondrial function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Pigino G, Morfini G, Pelsman A, Mattson MP, Brady ST, Busciglio J. Alzheimer’s presenilin 1 mutations impair kinesin-based axonal transport. J Neurosci. 2003;23(11):4499–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ittner LM, Ke YD, Gotz J. Phosphorylated tau interacts with c-Jun N-terminal kinase-interacting protein 1 (JIP1) in Alzheimer disease. J Biol Chem. 2009;284(31):20909–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Iijima-Ando K, Sekiya M, Maruko-Otake A, Ohtake Y, Suzuki E, Lu BW, et al. Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer’s disease-related tau phosphorylation via PAR-1. Plos Genetics. 2012;8(8).

  99. • Zhang L, Zhang S, Maezawa I, Trushin S, Minhas P, Pinto M, et al. Modulation of mitochondrial complex I activity averts cognitive decline in multiple animal models of familial Alzheimer's disease. EBioMedicine. 2015;2:294–305 Describing the use of small molecule partial inhibitors of mitochondrial complex I as a novel therapeutic strategy for AD.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Tammineni P, Jeong YY, Feng T, Aikal D, Cai Q. Impaired axonal retrograde trafficking of the retromer complex augments lysosomal deficits in Alzheimer's disease neurons. Hum Mol Genet. 2017;26(22):4352–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Rahman S, Archana A, Jan AT, Minakshi R. Dissecting endoplasmic reticulum unfolded protein response (UPR(ER)) in managing clandestine modus operandi of Alzheimer’s disease. Front Aging Neurosci. 2018;10:30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. •• Area-Gomez E, de Groof A, Bonilla E, Montesinos J, Tanji K, Boldogh I, et al. A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease. Cell Death Dis. 2018;9:335 Excellent review on the importance of mitochondrial associated membranes in AD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Hedskog L, Pinho CM, Filadi R, Ronnback A, Hertwig L, Wiehager B, et al. Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer’s disease and related models. Proc Natl Acad Sci U S A. 2013;110(19):7916–21.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Area-Gomez E, Castillo MDL, Tambini MD, Guardia-Laguarta C, de Groof AJC, Madra M, et al. Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J. 2012;31(21):4106–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Pera M, Larrea D, Guardia-Laguarta C, Montesinos J, Velasco KR, Agrawal RR, et al. Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO J. 2017;36(22):3356–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Yu J, Novgorodov SA, Chudakova D, Zhu H, Bielawska A, Bielawski J, et al. JNK3 signaling pathway activates ceramide synthase leading to mitochondrial dysfunction. J Biol Chem. 2007;282(35):25940–9.

    Article  CAS  PubMed  Google Scholar 

  107. Monette JS, Gomez LA, Moreau RF, Dunn KC, Butler JA, Finlay LA, et al. (R)-alpha-lipoic acid treatment restores ceramide balance in aging rat cardiac mitochondria. Pharmacol Res. 2011;63(1):23–9.

    Article  CAS  PubMed  Google Scholar 

  108. Trounce IA, Crouch PJ, Carey KT, McKenzie M. Modulation of ceramide-induced cell death and superoxide production by mitochondrial DNA-encoded respiratory chain defects in Rattus xenocybrid mouse cells. BBA-Bioenergetics. 2013;1827(7):817–25.

    Article  CAS  PubMed  Google Scholar 

  109. Zigdon H, Kogot-Levin A, Park JW, Goldschmidt R, Kelly S, Merrill AH Jr, et al. Ablation of ceramide synthase 2 causes chronic oxidative stress due to disruption of the mitochondrial respiratory chain. J Biol Chem. 2013;288:4947–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kogot-Levin A, Saada A. Ceramide and the mitochondrial respiratory chain. Biochimie. 2014;100:88–94.

    Article  CAS  PubMed  Google Scholar 

  111. Ji WK, Chakrabarti R, Fan XT, Schoenfeld L, Strack S, Higgs HN. Receptor-mediated Drp1 oligomerization on endoplasmic reticulum. J Cell Biol. 2017;216(12):4123–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sorrentino V, Omani MR, Ouchiroud LM, Beck JS, Zhang HB, D'Amico D, et al. Enhancing mitochondrial proteostasis reduces amyloid-beta proteotoxicity. Nature. 2017;552(7684):187–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Beck JS, Mufson EJ, Counts SE. Evidence for mitochondrial UPR gene activation in familial and sporadic Alzheimer’s disease. Curr Alzheimer Res. 2016;13(6):610–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Falkevall A, Alikhani N, Bhushan S, Pavlov PF, Busch K, Johnson KA, et al. Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP. J Biol Chem. 2006;281(39):29096–104.

    Article  CAS  PubMed  Google Scholar 

  115. Alikhani N, Guo L, Yan SQ, Du H, Pinho CM, Chen JX, et al. Decreased proteolytic activity of the mitochondrial amyloid-beta degrading enzyme, PreP peptidasome, in Alzheimer’s disease brain mitochondria. J Alzheimers Dis. 2011;27(1):75–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Gregori L, Fuchs C, Figueiredopereira ME, Vannostrand WE, Goldgaber D. Amyloid beta-protein inhibits ubiquitin-dependent protein-degradation in-vitro. J Biol Chem. 1995;270(34):19702–8.

    Article  CAS  PubMed  Google Scholar 

  117. Keller JN, Hanni KB, Markesbery WR. Impaired proteasome function in Alzheimer’s disease. J Neurochem. 2000;75(1):436–9.

    Article  CAS  PubMed  Google Scholar 

  118. Tseng BP, Green KN, Chan JL, Blurton-Jones M, LaFerla FM. A beta inhibits the proteasome and enhances amyloid and tau accumulation. Neurobiol Aging. 2008;29(11):1607–18.

    Article  CAS  PubMed  Google Scholar 

  119. • Palikaras K, Lionaki E, Tavernarakis N. Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat Cell Biol. 2018;20(9):1013–22 Excellent review on cellular quality control mechanisms.

    Article  CAS  PubMed  Google Scholar 

  120. 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. 2016;25(4):792–806.

    Article  CAS  PubMed  Google Scholar 

  121. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol. 2005;64(2):113–22.

    Article  PubMed  Google Scholar 

  122. Nixon RA. Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci. 2007;120(23):4081–91.

    Article  CAS  PubMed  Google Scholar 

  123. Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, et al. Macroautophagy—a novel beta-amyloid peptide-generating pathway activated in Alzheimer’s disease. J Cell Biol. 2005;171(1):87–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bordi M, Berg MJ, Mohan PS, Peterhoff CM, Alldred MJ, Che SL, et al. Autophagy flux in CA1 neurons of Alzheimer hippocampus: increased induction overburdens failing lysosomes to propel neuritic dystrophy. Autophagy. 2016;12(12):2467–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Ye X, Sun X, Starovoytov V, Cai Q. Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer’s disease patient brains. Hum Mol Genet. 2015.

  126. Reddy AP, Reddy PH. Mitochondria-targeted molecules as potential drugs to treat patients with Alzheimer’s disease. Prog Mol Biol Transl Sci. 2017;146:173–201.

    Article  CAS  PubMed  Google Scholar 

  127. Hara Y, McKeehan N, Fillit HM. Translating the biology of aging into novel therapeutics for Alzheimer disease. Neurology. 2019;92(2):84–93.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Rotermund C, Machetanz G, Fitzgerald JC. The therapeutic potential of metformin in neurodegenerative diseases. Front Endocrinol (Lausanne). 2018;9:400.

    Article  Google Scholar 

  129. Ribarič S. The rationale for insulin therapy in Alzheimer’s disease. Molecules. 2016;21(6).

  130. Jardim FR, de Rossi FT, Nascimento MX, da Silva Barros RG, Borges PA, Prescilio IC, et al. Resveratrol and brain mitochondria: a review. Mol Neurobiol. 2018;55(3):2085–101.

    Article  CAS  PubMed  Google Scholar 

  131. Goldberg J, Currais A, Prior M, Fischer W, Chiruta C, Ratliff E, et al. The mitochondrial ATP synthase is a shared drug target for aging and dementia. Aging Cell. 2018;17(2).

  132. Komaki H, Faraji N, Komaki A, Shahidi S, Etaee F, Raoufi S, Mirzaei F. Investigation of protective effects of coenzyme Q10 on impaired synaptic plasticity in a male rat model of Alzheimer's disease. Brain Res Bull. 2019;9:(147):14–21.

  133. Kumar A, Singh A. A review on mitochondrial restorative mechanism of antioxidants in Alzheimer’s disease and other neurological conditions. Front Pharmacol. 2015;6:206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T, et al. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell. 2008;14(2):193–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Christ MG, Huesmann H, Nagel H, Kern A, Behl C. Sigma-1 receptor activation induces autophagy and increases proteostasis capacity in vitro and in vivo. Cells. 2019;8(3).

  136. Hebron ML, Lonskaya I, Moussa CE. Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-synuclein in Parkinson’s disease models. Hum Mol Genet. 2013;22(16):3315–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Li W, Huang E. An update on type 2 diabetes mellitus as a risk factor for dementia. J Alzheimers Dis. 2016;53(2):393–402.

    Article  CAS  PubMed  Google Scholar 

  138. Searcy JL, Phelps JT, Pancani T, Kadish I, Popovic J, Anderson KL, et al. Long-term pioglitazone treatment improves learning and attenuates pathological markers in a mouse model of Alzheimer’s disease. J Alzheimers Dis. 2012;30(4):943–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Seok H, Lee M, Shin E, Yun MR, Lee YH, Moon JH, et al. Low-dose pioglitazone can ameliorate learning and memory impairment in a mouse model of dementia by increasing LRP1 expression in the hippocampus. Sci Rep. 2019;9(1):4414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Pedersen WA, McMillan PJ, Kulstad JJ, Leverenz JB, Craft S, Haynatzki GR. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol. 2006;199(2):265–73.

    Article  CAS  PubMed  Google Scholar 

  141. Escribano L, Simón AM, Pérez-Mediavilla A, Salazar-Colocho P, Del Río J, Frechilla D. Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer’s disease mouse model. Biochem Biophys Res Commun. 2009;379(2):406–10.

    Article  CAS  PubMed  Google Scholar 

  142. Toledo EM, Inestrosa NC. Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1DeltaE9 mouse model of Alzheimer’s disease. Mol Psychiatry. 2010;15(3):272–85 28.

    Article  CAS  PubMed  Google Scholar 

  143. O’Reilly JA, Lynch M. Rosiglitazone improves spatial memory and decreases insoluble Aβ(1-42) in APP/PS1 mice. J Neuroimmune Pharmacol. 2012;7(1):140–4.

    Article  PubMed  Google Scholar 

  144. Strum JC, Shehee R, Virley D, Richardson J, Mattie M, Selley P, et al. Rosiglitazone induces mitochondrial biogenesis in mouse brain. J Alzheimers Dis. 2007;11(1):45–51.

    Article  CAS  PubMed  Google Scholar 

  145. Bogacka I, Xie H, Bray GA, Smith SR. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes. 2005;54(5):1392–9.

    Article  CAS  PubMed  Google Scholar 

  146. Ghosh S, Patel N, Rahn D, McAllister J, Sadeghi S, Horwitz G, et al. The thiazolidinedione pioglitazone alters mitochondrial function in human neuron-like cells. Mol Pharmacol. 2007;71(6):1695–702.

    Article  CAS  PubMed  Google Scholar 

  147. Gold M, Alderton C, Zvartau-Hind M, Egginton S, Saunders AM, Irizarry M, et al. Rosiglitazone monotherapy in mild-to-moderate Alzheimer’s disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord. 2010;30(2):131–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Koenig AM, Mechanic-Hamilton D, Xie SX, Combs MF, Cappola AR, Xie L, et al. Effects of the insulin sensitizer metformin in Alzheimer disease: pilot data from a randomized placebo-controlled crossover study. Alzheimer Dis Assoc Disord. 2017;31(2):107–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Craft S, Claxton A, Baker LD, Hanson AJ, Cholerton B, Trittschuh EH, et al. Effects of regular and long-acting insulin on cognition and Alzheimer’s disease biomarkers: a pilot clinical trial. J Alzheimers Dis. 2017;57(4):1325–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Zhong KL, Chen F, Hong H, Ke X, Lv YG, Tang SS, et al. New views and possibilities of antidiabetic drugs in treating and/or preventing mild cognitive impairment and Alzheimer’s disease. Metab Brain Dis. 2018;33(4):1009–18.

    Article  CAS  PubMed  Google Scholar 

  151. Gomes BAQ, Silva JPB, Romeiro CFR, Dos Santos SM, Rodrigues CA, Gonçalves PR, et al. Neuroprotective mechanisms of resveratrol in Alzheimer’s disease: role of SIRT1. Oxidative Med Cell Longev. 2018;2018:8152373.

    Article  Google Scholar 

  152. Madrigal-Perez LA, Ramos-Gomez M. Resveratrol inhibition of cellular respiration: new paradigm for an old mechanism. Int J Mol Sci. 2016;17(3):368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Sawda C, Moussa C, Turner RS. Resveratrol for Alzheimer’s disease. Ann N Y Acad Sci. 2017;1403(1):142–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Reddy PH, Tripathi R, Troung Q, Tirumala K, Reddy TP, Anekonda V, et al. Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer’s disease: implications to mitochondria-targeted antioxidant therapeutics. Biochim Biophys Acta. 2012;1822(5):639–49.

    Article  CAS  PubMed  Google Scholar 

  155. Feniouk BA, Skulachev VP. Cellular and molecular mechanisms of action of mitochondria-targeted antioxidants. Curr Aging Sci. 2017;10:41–8.

    Article  CAS  PubMed  Google Scholar 

  156. Reddy PH, Manczak M, Yin X. Mitochondria-division inhibitor 1 protects against amyloid-β induced mitochondrial fragmentation and synaptic damage in Alzheimer’s disease. J Alzheimers Dis. 2017;58(1):147–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Reddy PH, Manczak M, Yin X, Reddy AP. Synergistic protective effects of mitochondrial division inhibitor 1 and mitochondria-targeted Small peptide SS31 in Alzheimer's disease. J Alzheimers Dis. 2018;62(4):1549–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Wang W, Yin J, Ma X, Zhao F, Siedlak SL, Wang Z, et al. Inhibition of mitochondrial fragmentation protects against Alzheimer’s disease in rodent model. Hum Mol Genet. 2017;26:4118–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Baek SH, Park SJ, Jeong JI, Kim SH, Han J, Kyung JW, et al. Inhibition of Drp1 ameliorates synaptic depression, Aβ deposition, and cognitive impairment in an Alzheimer’s disease model. J Neurosci. 2017;37(20):5099–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Smith G, Gallo G. To mdivi-1 or not to mdivi-1: is that the question? Dev Neurobiol. 2017;77(11):1260–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Lonskaya I, Hebron ML, Desforges NM, Franjie A, Moussa CE. Tyrosine kinase inhibition increases functional Parkin-Beclin-1 interaction and enhances amyloid clearance and cognitive performance. EMBO Mol Med. 2013;5(8):1247–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Baumgart M, Snyder HM, Carrillo MC, Fazio S, Kim H, Johns H. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective. Alzheimers Dement. 2015;11(6):718–26.

    Article  PubMed  Google Scholar 

  163. Bertram S, Brixius K, Brinkmann C. Exercise for the diabetic brain: how physical training may help prevent dementia and Alzheimer’s disease in T2DM patients. Endocrine. 2016;53(2):350–63.

    Article  CAS  PubMed  Google Scholar 

  164. Baker LD, Frank LL, Foster-Schubert K, Green PS, Wilkinson CW, McTiernan A, et al. Aerobic exercise improves cognition for older adults with glucose intolerance, a risk factor for Alzheimer’s disease. J Alzheimers Dis. 2010;22(2):569–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Mendiola-Precoma J, Berumen LC, Padilla K, Garcia-Alcocer G. Therapies for prevention and treatment of Alzheimer’s disease. Biomed Res Int. 2016;2016:2589276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Ntsapi C, Loos B. Caloric restriction and the precision-control of autophagy: a strategy for delaying neurodegenerative disease progression. Exp Gerontol. 2016;83:97–111.

    Article  CAS  PubMed  Google Scholar 

  167. Van Cauwenberghe C, Vandendriessche C, Libert C, Vandenbroucke RE. Caloric restriction: beneficial effects on brain aging and Alzheimer’s disease. Mamm Genome. 2016;27(7–8):300–19.

    Article  CAS  PubMed  Google Scholar 

  168. •• Ngandu T, Lehtisalo J, Solomon A, Levalahti E, Ahtiluoto S, Antikainen R, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015;385(9984):2255–63 Current investigative trials on modifiable risk factors for AD.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Padraig J. Flannery & Eugenia Trushina

  2. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA

    Eugenia Trushina

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  1. Padraig J. Flannery
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Glossary

UPRmt

mitochondrial unfolded protein response

3D EM

three-dimensional electron microscopy;

3-NT

3-nitrotyrosine, a product of nitrosative stress in cells;

AD

Alzheimer’s disease;

AMPK

Adenosine Monophosphate (AMP)-activated protein kinase;

Anavex 2-73

tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine;

APP

amyloid precursor protein;

ARE

antioxidant response element, which plays a critical role in the protection against oxidative stress and maintenance of redox homeostasis;

ATP

adenosine triphosphate;

Aβ

amyloid-β peptide;

Bioenergetics

a biochemical process of cellular energy production, storage and utilization;

CT1812

sigma-2 receptor complex allosteric antagonist;

Cybrids

cell lines that maintain the same nuclear DNA but differ in mitochondrial DNA;

DRP1

Dynamin-related protein 1;

ER

endoplasmic reticulum;

ETC

electron transport chain consisting of mitochondrial complexes I–IV that maintain electron flow and proton gradient essential for the ATP production by mitochondrial complex V;

FDA

the US Food and Drug Administration;

FDG-PET

fluorodeoxyglucose-positron emission tomography;

GPX

glutathione peroxidase;

GSK-3β

Glycogen synthase kinase 3 beta;

GTPases

a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP);

HNE

4-hydroxyl-2-trans-nonenal, a product of oxidative stress in cells;

IMM

inner mitochondrial membranes;

JIP1

c-Jun N-terminal kinase-interacting protein 1;

MAM

mitochondria-associated membranes;

MCI

mild cognitive impairment, a prodromal stage of AD;

Mdivi-1

Mitochondrial division inhibitor 1;

MFN1

Mitofusin 1 protein;

MFN2

Mitofusin 2 protein;

Mitochondrial biogenesis

the regulated process that increases mitochondrial mass;

Mitochondrial fission

the ability of organelles to divide in response to environmental changes;

Mitochondrial fusion

the ability of organelles to fuse together in response to environmental changes;

Mitochondrial haplotypes

specific regions of mtDNA that cluster with other mitochondrial sequences to show the phylogenetic origins of maternal lineages;

Mitohormesis

the mitochondrial signaling via ROS molecules that promotes health by preventing or delaying a number of chronic diseases;

Mitophagy

the process of removal of damages organelles by lysosomal degradation;

MitoQ

mitoquinone mesylate;

MitoTEMPOL

mitochondria-targeting superoxide dismutase mimetic;

MitoVitE

mitotocopherol;

MOAS

mitochondria-on-a-string;

mtDNA

mitochondrial DNA;

NADH

nicotinamide adenine dinucleotide;

Nrf-1and Nrf-2

nuclear factor erythroid-derived 2-related factor 1 and 2;

OMM

outer mitochondrial membranes;

OPA1

Optic atrophy 1 protein;

OXPHOS complexes

complex I (nicotinamide adenine dinucleotide [NADH] dehydrogenase), complex II (succinate dehydrogenase), complex III (cytochrome C reductase), complex IV (cytochrome C oxidase [COX]), and complex V (ATP synthase);

OXPHOS

oxidative phosphorylation;

Parkin

an E3 ubiquitin ligase that promotes the covalent ubiquitination of molecules tagging them for degradation in proteasomes or lysosomes;

Pink1

PTEN-induced kinase 1, a mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene;

PreP

pre-sequence protease;

PS1

presenilin 1;

PS2

presenilin 2, mutations in APP, PS1 and PS2 proteins, all of which are involved in processing of amyloid beta peptides, are linked to familial AD;

pTau

phospho Tau protein;

Redox state

the ratio of the interconvertible oxidized and reduced form of a specific redox couple;

RNS

reactive nitrogen species;

ROS

reactive oxygen species;

SNPs

single nucleotide polymorphisms are variations in a single base pair in a DNA sequence;

SOD

superoxide dismutase;

SS peptides

Szeto-Schiller peptide antioxidants;

Synaptosomes

an enriched fraction of synaptic proteins and synaptic mitochondria isolated from neurons or brain tissue;

TCA

tricarboxylic acid cycle

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Flannery, P.J., Trushina, E. Mitochondrial Dysfunction in Alzheimer’s Disease and Progress in Mitochondria-Targeted Therapeutics. Curr Behav Neurosci Rep 6, 88–102 (2019). https://doi.org/10.1007/s40473-019-00179-0

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