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Targeting Mitochondria in Alzheimer Disease: Rationale and Perspectives

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Abstract

A decline in mitochondrial function plays a key role in the aging process and increases the incidence of age-related disorders, including Alzheimer disease (AD). Mitochondria—the power station of the organism—can affect several different cellular activities, including abnormal cellular energy generation, response to toxic insults, regulation of metabolism, and execution of cell death. In AD subjects, mitochondria are characterized by impaired function such as lowered oxidative phosphorylation, decreased adenosine triphosphate production, significant increased reactive oxygen species generation, and compromised antioxidant defense. The current review discusses the most relevant mitochondrial defects that are considered to play a significant role in AD and that may offer promising therapeutic targets for the treatment/prevention of AD. In addition, we discuss mechanisms of action and translational potential of some promising mitochondrial and bioenergetic therapeutics for AD including compounds able to potentiate energy production, antioxidants to scavenge reactive oxygen species and reduce oxidative damage, glucose metabolism, and candidates that target mitophagy. While mitochondrial therapeutic strategies have shown promise at the preclinical stage, there has been little progress in clinical trials. Thus, there is an urgent need to better understand the mechanisms regulating mitochondrial homeostasis in order to identify powerful drug candidates that target ‘in and out’ the mitochondria to preserve cognitive functions.

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References

  1. Alzheimer’s Disease Facts and Figures. 2019.

  2. Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer disease. Nat Rev Neurol. 2011;7(3):137–52.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Roher AE, Lowenson JD, Clarke S, Woods AS, Cotter RJ, Gowing E, et al. beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. Proc Natl Acad Sci USA. 1993;90(22):10836–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Small SA, Duff K. Linking A beta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron. 2008;60(4):534–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Morris JC, Cummings J. Mild cognitive impairment (MCI) represents early-stage Alzheimer’s disease. J Alzheimers Dis. 2005;7(3):235–9 (discussion 55–62).

    Article  PubMed  Google Scholar 

  6. Price JL, Morris JC. Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol. 1999;45(3):358–68.

    Article  CAS  PubMed  Google Scholar 

  7. Cimini FA, Arena A, Barchetta I, Tramutola A, Ceccarelli V, Lanzillotta C, et al. Reduced biliverdin reductase-A levels are associated with early alterations of insulin signaling in obesity. Biochim Biophys Acta Mol Basis Dis. 2019;1865(6):1490–501.

    Article  CAS  PubMed  Google Scholar 

  8. Asadbegi M, Yaghmaei P, Salehi I, Ebrahim-Habibi A, Komaki A. Neuroprotective effects of metformin against Abeta-mediated inhibition of long-term potentiation in rats fed a high-fat diet. Brain Res Bull. 2016;121:178–85.

    Article  CAS  PubMed  Google Scholar 

  9. Moreira PI, Cardoso SM, Santos MS, Oliveira CR. The key role of mitochondria in Alzheimer’s disease. J Alzheimers Dis. 2006;9(2):101–10.

    Article  CAS  PubMed  Google Scholar 

  10. Butterfield DA, Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci. 2019;20(3):148–60.

    Article  CAS  PubMed  Google Scholar 

  11. Moreira PI, Santos MS, Oliveira CR. Alzheimer’s disease: a lesson from mitochondrial dysfunction. Antioxid Redox Signal. 2007;9(10):1621–30.

    Article  CAS  PubMed  Google Scholar 

  12. Obulesu M, Lakshmi MJ. Apoptosis in Alzheimer’s disease: an understanding of the physiology, pathology and therapeutic avenues. Neurochem Res. 2014;39(12):2301–12.

    Article  CAS  PubMed  Google Scholar 

  13. Hauptmann S, Scherping I, Drose S, Brandt U, Schulz KL, Jendrach M, et al. Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging. 2009;30(10):1574–86.

    Article  CAS  PubMed  Google Scholar 

  14. Gordon BA, Blazey TM, Su Y, Hari-Raj A, Dincer A, Flores S, et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol. 2018;17(3):241–50.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Tang J, Oliveros A, Jang MH. Dysfunctional mitochondrial bioenergetics and synaptic degeneration in Alzheimer disease. Int Neurourol J. 2019;23(Suppl 1):S5–10.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Dominy JE, Puigserver P. Mitochondrial biogenesis through activation of nuclear signaling proteins. Csh Perspect Biol. 2013;5(7).

  17. Bhat AH, Dar KB, Anees S, Zargar MA, Masood A, Sofi MA, et al. Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed Pharmacother Biomed Pharmacother. 2015;74:101–10.

    Article  CAS  PubMed  Google Scholar 

  18. Butterfield DA, Gu L, Di Domenico F, Robinson RA. Mass spectrometry and redox proteomics: applications in disease. Mass Spectrom Rev. 2014;33(4):277–301.

    Article  CAS  PubMed  Google Scholar 

  19. Reed T, Perluigi M, Sultana R, Pierce WM, Klein JB, Turner DM, et al. Redox proteomic identification of 4-hydroxy-2-nonenal-modified brain proteins in amnestic mild cognitive impairment: insight into the role of lipid peroxidation in the progression and pathogenesis of Alzheimer’s disease. Neurobiol Dis. 2008;30(1):107–20.

    Article  CAS  PubMed  Google Scholar 

  20. Sultana R, Perluigi M, Butterfield DA. Lipid peroxidation triggers neurodegeneration: a redox proteomics view into the Alzheimer disease brain. Free Radic Biol Med. 2013;62:157–69.

    Article  CAS  PubMed  Google Scholar 

  21. Sultana R, Boyd-Kimball D, Poon HF, Cai J, Pierce WM, Klein JB, et al. Redox proteomics identification of oxidized proteins in Alzheimer’s disease hippocampus and cerebellum: an approach to understand pathological and biochemical alterations in AD. Neurobiol Aging. 2006;27(11):1564–76.

    Article  CAS  PubMed  Google Scholar 

  22. Perluigi M, Sultana R, Cenini G, Di Domenico F, Memo M, Pierce WM, et al. Redox proteomics identification of 4-hydroxynonenal-modified brain proteins in Alzheimer’s disease: role of lipid peroxidation in Alzheimer’s disease pathogenesis. Proteom Clin Appl. 2009;3(6):682–93.

    Article  CAS  Google Scholar 

  23. Reed TT, Pierce WM, Markesbery WR, Butterfield DA. Proteomic identification of HNE-bound proteins in early Alzheimer disease: insights into the role of lipid peroxidation in the progression of AD. Brain Res. 2009;5(1274):66–76.

    Article  CAS  Google Scholar 

  24. Aluise CD, Robinson RA, Cai J, Pierce WM, Markesbery WR, Butterfield DA. Redox proteomics analysis of brains from subjects with amnestic mild cognitive impairment compared to brains from subjects with preclinical Alzheimer’s disease: insights into memory loss in MCI. J Alzheimers Dis. 2011;23(2):257–69.

    Article  CAS  PubMed  Google Scholar 

  25. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  26. Bilsland LG, Nirmalananthan N, Yip J, Greensmith L, Duchen MR. Expression of mutant SOD1 in astrocytes induces functional deficits in motoneuron mitochondria. J Neurochem. 2008;107(5):1271–83.

    Article  CAS  PubMed  Google Scholar 

  27. Casley CS, Land JM, Sharpe MA, Clark JB, Duchen MR, Canevari L. Beta-amyloid fragment 25–35 causes mitochondrial dysfunction in primary cortical neurons. Neurobiol Dis. 2002;10(3):258–67.

    Article  CAS  PubMed  Google Scholar 

  28. Sheng ZH, Cai Q. Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat Rev Neurosci. 2012;13(2):77–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cai Q, Gerwin C, Sheng ZH. Syntabulin-mediated anterograde transport of mitochondria along neuronal processes. J Cell Biol. 2005;170(6):959–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hirokawa N, Niwa S, Tanaka Y. Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease. Neuron. 2010;68(4):610–38.

    Article  CAS  PubMed  Google Scholar 

  31. Stokin GB, Goldstein LS. Axonal transport and Alzheimer’s disease. Annu Rev Biochem. 2006;75:607–27.

    Article  CAS  PubMed  Google Scholar 

  32. Nicholson RM, Kusne Y, Nowak LA, LaFerla FM, Reiman EM, Valla J. Regional cerebral glucose uptake in the 3xTG model of Alzheimer’s disease highlights common regional vulnerability across AD mouse models. Brain Res. 2010;6(1347):179–85.

    Article  CAS  Google Scholar 

  33. Mosconi L, De Santi S, Li J, Tsui WH, Li Y, Boppana M, et al. Hippocampal hypometabolism predicts cognitive decline from normal aging. Neurobiol Aging. 2008;29(5):676–92.

    Article  CAS  PubMed  Google Scholar 

  34. Cardoso SM, Proenca MT, Santos S, Santana I, Oliveira CR. Cytochrome c oxidase is decreased in Alzheimer’s disease platelets. Neurobiol Aging. 2004;25(1):105–10.

    Article  CAS  PubMed  Google Scholar 

  35. Dumont M, Beal MF. Neuroprotective strategies involving ROS in Alzheimer disease. Free Radic Biol Med. 2011;51(5):1014–26.

    Article  CAS  PubMed  Google Scholar 

  36. Reddy PH, Beal MF. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol Med. 2008;14(2):45–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta. 2014;1842(8):1240–7.

    Article  CAS  PubMed  Google Scholar 

  38. Gottlieb RA, Carreira RS. Autophagy in health and disease. 5. Mitophagy as a way of life. Am J Physiol Cell Physiol. 2010;299(2):C203–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Onyango IG, Dennis J, Khan SM. Mitochondrial dysfunction in Alzheimer’s disease and the rationale for bioenergetics based therapies. Aging Dis. 2016;7(2):201–14.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Caldwell CC, Yao J, Brinton RD. Targeting the prodromal stage of Alzheimer’s disease: bioenergetic and mitochondrial opportunities. Neurotherapeutics. 2015;12(1):66–80.

    Article  CAS  PubMed  Google Scholar 

  41. Hu H, Tan CC, Tan L, Yu JT. A mitocentric view of Alzheimer’s disease. Mol Neurobiol. 2017;54(8):6046–60.

    Article  CAS  PubMed  Google Scholar 

  42. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, et al. Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci. 2001;21(9):3017–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Swerdlow RH, Burns JM, Khan SM. The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives. Biochim Biophys Acta. 2014;1842(8):1219–31.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  45. 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 Apr;17(2).

  46. Chen Q, Prior M, Dargusch R, Roberts A, Riek R, Eichmann C, et al. A novel neurotrophic drug for cognitive enhancement and Alzheimer’s disease. PLoS One. 2011;6(12):e27865.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Currais A, Goldberg J, Farrokhi C, Chang M, Prior M, Dargusch R, et al. A comprehensive multiomics approach toward understanding the relationship between aging and dementia. Aging (Albany NY). 2015;7(11):937–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Prior M, Chiruta C, Currais A, Goldberg J, Ramsey J, Dargusch R, et al. Back to the future with phenotypic screening. ACS Chem Neurosci. 2014;5(7):503–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Das AM. Regulation of the mitochondrial ATP-synthase in health and disease. Mol Genet Metab. 2003;79(2):71–82.

    Article  CAS  PubMed  Google Scholar 

  50. Formentini L, Sanchez-Arago M, Sanchez-Cenizo L, Cuezva JM. The mitochondrial ATPase inhibitory factor 1 triggers a ROS-mediated retrograde prosurvival and proliferative response. Mol Cell. 2012;45(6):731–42.

    Article  CAS  PubMed  Google Scholar 

  51. Ristow M. Unraveling the truth about antioxidants: mitohormesis explains ROS-induced health benefits. Nat Med. 2014;20(7):709–11.

    Article  CAS  PubMed  Google Scholar 

  52. 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 

  53. Yun J, Finkel T. Mitohormesis. Cell Metab. 2014;19(5):757–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Finkel T. The metabolic regulation of aging. Nat Med. 2015;21(12):1416–23.

    Article  CAS  PubMed  Google Scholar 

  55. Lopez-Otin C, Galluzzi L, Freije JMP, Madeo F, Kroemer G. Metabolic control of longevity. Cell. 2016;166(4):802–21.

    Article  CAS  PubMed  Google Scholar 

  56. Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, et al. The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014;510(7505):397–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sun X, Wheeler CT, Yolitz J, Laslo M, Alberico T, Sun Y, et al. A mitochondrial ATP synthase subunit interacts with TOR signaling to modulate protein homeostasis and lifespan in Drosophila. Cell Rep. 2014;8(6):1781–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Perluigi M, Di Domenico F, Butterfield DA. mTOR signaling in aging and neurodegeneration: at the crossroad between metabolism dysfunction and impairment of autophagy. Neurobiol Dis. 2015;84:39–49.

    Article  CAS  PubMed  Google Scholar 

  59. Tramutola A, Triplett JC, Di Domenico F, Niedowicz DM, Murphy MP, Coccia R, et al. Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD. J Neurochem. 2015;133(5):739–49.

    Article  CAS  PubMed  Google Scholar 

  60. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493(7432):338–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13(4):251–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhang C, Rissman RA, Feng J. Characterization of ATP alternations in an Alzheimer’s disease transgenic mouse model. J Alzheimers Dis. 2015;44(2):375–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 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 

  64. Gibson GE, Shi Q. A mitocentric view of Alzheimer’s disease suggests multi-faceted treatments. J Alzheimers Dis. 2010;20(Suppl 2):S591–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD. Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA. 2009;106(34):14670–5.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Bedse G, Di Domenico F, Serviddio G, Cassano T. Aberrant insulin signaling in Alzheimer’s disease: current knowledge. Front Neurosci. 2015;9:204.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Biessels GJ, Reagan LP. Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci. 2015;16(11):660–71.

    Article  CAS  PubMed  Google Scholar 

  68. Barone E, Tramutola A, Triani F, Calcagnini S, Di Domenico F, Ripoli C, et al. Biliverdin reductase-a mediates the beneficial effects of intranasal insulin in alzheimer disease. Mol Neurobiol. 2019;56(4):2922–43.

    Article  CAS  PubMed  Google Scholar 

  69. de la Monte SM. Relationships between diabetes and cognitive impairment. Endocrin Metab Clin. 2014;43(1):245.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  71. Schioth HB, Craft S, Brooks SJ, Frey WH 2nd, Benedict C. Brain insulin signaling and Alzheimer’s disease: current evidence and future directions. Mol Neurobiol. 2012;46(1):4–10.

    Article  CAS  PubMed  Google Scholar 

  72. Benedict C, Frey WH, Schioth HB, Schultes B, Born J, Hallschmid M. Intranasal insulin as a therapeutic option in the treatment of cognitive impairments. Exp Gerontol. 2011;46(2–3):112–5.

    Article  CAS  PubMed  Google Scholar 

  73. Chen Y, Zhao Y, Dai CL, Liang Z, Run X, Iqbal K, et al. Intranasal insulin restores insulin signaling, increases synaptic proteins, and reduces Abeta level and microglia activation in the brains of 3xTg-AD mice. Exp Neurol. 2014;261:610–9.

    Article  CAS  PubMed  Google Scholar 

  74. Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012;69(1):29–38.

    Article  PubMed  Google Scholar 

  75. Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis. 2008;13(3):323–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology. 2008;70(6):440–8.

    Article  CAS  PubMed  Google Scholar 

  77. Claxton A, Baker LD, Hanson A, Trittschuh EH, Cholerton B, Morgan A, et al. Long acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease dementia. J Alzheimers Dis. 2015;45(4):1269–70.

    Article  PubMed  Google Scholar 

  78. Liu F, Shi J, Tanimukai H, Gu J, Gu J, Grundke-Iqbal I, et al. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer’s disease. Brain. 2009;132(Pt 7):1820–32.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Hart GW. Nutrient regulation of signaling and transcription. J Biol Chem. 2019;294(7):2211–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Akan I, Olivier-Van Stichelen S, Bond MR, Hanover JA. Nutrient-driven O-GlcNAc in proteostasis and neurodegeneration. J Neurochem. 2018;144(1):7–34.

    Article  CAS  PubMed  Google Scholar 

  81. Pinho TS, Correia SC, Perry G, Ambrosio AF, Moreira PI. Diminished O-GlcNAcylation in Alzheimer’s disease is strongly correlated with mitochondrial anomalies. Biochim Biophys Acta Mol Basis Dis. 2018.

  82. Cha MY, Cho HJ, Kim C, Jung YO, Kang MJ, Murray ME, et al. Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer’s disease. Hum Mol Genet. 2015;24(22):6492–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Tan EP, Villar MT, Lezi E, Lu J, Selfridge JE, Artigues A, et al. Altering O-linked beta-N-acetylglucosamine cycling disrupts mitochondrial function. J Biol Chem. 2014;289(21):14719–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Di Domenico F, Lanzillotta C, Tramutola A. Therapeutic potential of rescuing protein O-GlcNAcylation in tau-related pathologies. Expert Rev Neurother. 2019;19(1):1–3.

    Article  CAS  PubMed  Google Scholar 

  85. Zhu YP, Shan XY, Yuzwa SA, Vocadlo DJ. The emerging link between O-GlcNAc and Alzheimer disease. J Biol Chem. 2014;289(50):34472–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Yuzwa SA, Shan X, Jones BA, Zhao G, Woodward ML, Li X, et al. Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice. Mol Neurodegener. 2014;26(9):42.

    Article  Google Scholar 

  87. Yuzwa SA, Vocadlo DJ. O-GlcNAc and neurodegeneration: biochemical mechanisms and potential roles in Alzheimer’s disease and beyond. Chem Soc Rev. 2014;43(19):6839–58.

    Article  CAS  PubMed  Google Scholar 

  88. Di Domenico F, Barone E, Perluigi M, Butterfield DA. Strategy to reduce free radical species in Alzheimer’s disease: an update of selected antioxidants. Expert Rev Neurother. 2015;15(1):19–40.

    Article  CAS  PubMed  Google Scholar 

  89. Reddy PH. Mitochondrial oxidative damage in aging and Alzheimer’s disease: implications for mitochondrially targeted antioxidant therapeutics. J Biomed Biotechnol. 2006;2006(3):31372.

    PubMed  PubMed Central  Google Scholar 

  90. Perkins AJ, Hendrie HC, Callahan CM, Gao S, Unverzagt FW, Xu Y, et al. Association of antioxidants with memory in a multiethnic elderly sample using the Third National Health and Nutrition Examination Survey. Am J Epidemiol. 1999;150(1):37–44.

    Article  CAS  PubMed  Google Scholar 

  91. Kontush A, Mann U, Arlt S, Ujeyl A, Luhrs C, Muller-Thomsen T, et al. Influence of vitamin E and C supplementation on lipoprotein oxidation in patients with Alzheimer’s disease. Free Radic Biol Med. 2001;31(3):345–54.

    Article  CAS  PubMed  Google Scholar 

  92. Fillenbaum GG, Kuchibhatla MN, Hanlon JT, Artz MB, Pieper CF, Schmader KE, et al. Dementia and Alzheimer’s disease in community-dwelling elders taking vitamin C and/or vitamin E. Ann Pharmacother. 2005;39(12):2009–14.

    Article  CAS  PubMed  Google Scholar 

  93. Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014;311(1):33–44.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Shetty RA, Ikonne US, Forster MJ, Sumien N. Coenzyme Q10 and alpha-tocopherol reversed age-associated functional impairments in mice. Exp Gerontol. 2014;58:208–18.

    Article  CAS  PubMed  Google Scholar 

  95. Maczurek A, Hager K, Kenklies M, Sharman M, Martins R, Engel J, et al. Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer’s disease. Adv Drug Deliv Rev. 2008;60(13–14):1463–70.

    Article  CAS  PubMed  Google Scholar 

  96. Hager K, Kenklies M, McAfoose J, Engel J, Munch G. alpha-Lipoic acid as a new treatment option for Alzheimer’s disease—a 48 months follow-up analysis. J Neural Transm Supp. 2007;72:189–93.

    CAS  Google Scholar 

  97. Hager K, Marahrens A, Kenklies M, Riederer P, Munich G. Alpha-lipoic acid as a new treatment option for Alzheimer type dementia (vol 32, pg 275, 2001). Arch Gerontol Geriatr. 2010;51(1):110.

    Article  Google Scholar 

  98. Beal MF. Mitochondrial dysfunction and oxidative damage in Alzheimer’s and Parkinson’s diseases and coenzyme Q10 as a potential treatment. J Bioenerg Biomembr. 2004;36(4):381–6.

    Article  CAS  PubMed  Google Scholar 

  99. Moreira PI, Zhu X, Wang X, Lee HG, Nunomura A, Petersen RB, et al. Mitochondria: a therapeutic target in neurodegeneration. Biochim Biophys Acta. 2010;1802(1):212–20.

    Article  CAS  PubMed  Google Scholar 

  100. Yang X, Yang Y, Li G, Wang J, Yang ES. Coenzyme Q10 attenuates beta-amyloid pathology in the aged transgenic mice with Alzheimer presenilin 1 mutation. J Mol Neurosci. 2008;34(2):165–71.

    Article  CAS  PubMed  Google Scholar 

  101. McManus MJ, Murphy MP, Franklin JL. 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. 2011;31(44):15703–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Smith RA, Hartley RC, Cocheme HM, Murphy MP. Mitochondrial pharmacology. Trends Pharmacol Sci. 2012;33(6):341–52.

    Article  CAS  PubMed  Google Scholar 

  103. Ng LF, Gruber J, Cheah IK, Goo CK, Cheong WF, Shui G, et al. The mitochondria-targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease. Free Radic Biol Med. 2014;71:390–401.

    Article  CAS  PubMed  Google Scholar 

  104. Handschin C, Spiegelman BM. The role of exercise and PGC1alpha in inflammation and chronic disease. Nature. 2008;454(7203):463–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Canto C, Auwerx J. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol. 2009;20(2):98–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Verdin E, Hirschey MD, Finley LW, Haigis MC. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci. 2010;35(12):669–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Canugovi C, Maynard S, Bayne AC, Sykora P, Tian J, de Souza-Pinto NC, et al. The mitochondrial transcription factor A functions in mitochondrial base excision repair. DNA Repair (Amst). 2010;9(10):1080–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sheng B, Wang X, Su B, Lee HG, Casadesus G, Perry G, et al. Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer’s disease. J Neurochem. 2012;120(3):419–29.

    Article  CAS  PubMed  Google Scholar 

  109. Suliman HB, Piantadosi CA. Mitochondrial biogenesis: regulation by endogenous gases during inflammation and organ stress. Curr Pharm Des. 2014;20(35):5653–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Pallas M, Casadesus G, Smith MA, Coto-Montes A, Pelegri C, Vilaplana J, et al. Resveratrol and neurodegenerative diseases: activation of SIRT1 as the potential pathway towards neuroprotection. Curr Neurovasc Res. 2009;6(1):70–81.

    Article  CAS  PubMed  Google Scholar 

  111. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005;434(7029):113–8.

    Article  CAS  PubMed  Google Scholar 

  112. Um JH, Park SJ, Kang H, Yang S, Foretz M, McBurney MW, et al. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes. 2010;59(3):554–63.

    Article  CAS  PubMed  Google Scholar 

  113. Guida N, Laudati G, Anzilotti S, Secondo A, Montuori P, Di Renzo G, et al. Resveratrol via sirtuin-1 downregulates RE1-silencing transcription factor (REST) expression preventing PCB-95-induced neuronal cell death. Toxicol Appl Pharmacol. 2015;288(3):387–98.

    Article  CAS  PubMed  Google Scholar 

  114. Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H, Yi S, et al. SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem. 2005;280(48):40364–74.

    Article  CAS  PubMed  Google Scholar 

  115. Zhao YN, Li WF, Li F, Zhang Z, Dai YD, Xu AL, et al. Resveratrol improves learning and memory in normally aged mice through microRNA-CREB pathway. Biochem Biophys Res Commun. 2013;435(4):597–602.

    Article  CAS  PubMed  Google Scholar 

  116. Rege SD, Geetha T, Griffin GD, Broderick TL, Babu JR. Neuroprotective effects of resveratrol in Alzheimer disease pathology. Front Aging Neurosci. 2014;6:218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Wang R, Zhang Y, Li J, Zhang C. Resveratrol ameliorates spatial learning memory impairment induced by Abeta1–42 in rats. Neuroscience. 2017;6(344):39–47.

    Article  CAS  Google Scholar 

  118. Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology. 2015;85(16):1383–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Sanders MJ, Grondin PO, Hegarty BD, Snowden MA, Carling D. Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J. 2007;403(1):139–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kickstein E, Krauss S, Thornhill P, Rutschow D, Zeller R, Sharkey J, et al. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc Natl Acad Sci USA. 2010;107(50):21830–5.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Wang J, Gallagher D, DeVito LM, Cancino GI, Tsui D, He L, et al. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell. 2012;11(1):23–35.

    Article  CAS  PubMed  Google Scholar 

  122. Chen F, Dong RR, Zhong KL, Ghosh A, Tang SS, Long Y, et al. Antidiabetic drugs restore abnormal transport of amyloid-beta across the blood-brain barrier and memory impairment in db/db mice. Neuropharmacology. 2016;101:123–36.

    Article  CAS  PubMed  Google Scholar 

  123. Chiang MC, Cheng YC, Chen SJ, Yen CH, Huang RN. Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against Amyloid-beta-induced mitochondrial dysfunction. Exp Cell Res. 2016;347(2):322–31.

    Article  CAS  PubMed  Google Scholar 

  124. Geisler JG, Marosi K, Halpern J, Mattson MP. DNP, mitochondrial uncoupling, and neuroprotection: a little dab’ll do ya. Alzheimers Dement. 2017;13(5):582–91.

    Article  PubMed  Google Scholar 

  125. Ghavami S, Shojaei S, Yeganeh B, Ande SR, Jangamreddy JR, Mehrpour M, et al. Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol. 2014;112:24–49.

    Article  CAS  PubMed  Google Scholar 

  126. Shefa U, Jeong NY, Song IO, Chung HJ, Kim D, Jung J, et al. Mitophagy links oxidative stress conditions and neurodegenerative diseases. Neural Regen Res. 2019;14(5):749–56.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Okazawa H, Ikawa M, Tsujikawa T, Kiyono Y, Yoneda M. Brain imaging for oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Q J Nucl Med Mol Imaging. 2014;58(4):387–97.

    CAS  PubMed  Google Scholar 

  128. Cadenas E. Mitochondrial free radical production and cell signaling. Mol Aspects Med. 2004;25(1–2):17–26.

    Article  CAS  PubMed  Google Scholar 

  129. Rubinsztein DC, Shpilka T, Elazar Z. Mechanisms of autophagosome biogenesis. Curr Biol. 2012;22(1):R29–34.

    Article  CAS  PubMed  Google Scholar 

  130. Schieke SM, Finkel T. Mitochondrial signaling, TOR, and life span. Biol Chem. 2006;387(10–11):1357–61.

    CAS  PubMed  Google Scholar 

  131. Yang DS, Stavrides P, Mohan PS, Kaushik S, Kumar A, Ohno M, et al. Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer’s disease ameliorates amyloid pathologies and memory deficits. Brain. 2011;134(Pt 1):258–77.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  133. Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med. 2013;19(8):983–97.

    Article  CAS  PubMed  Google Scholar 

  134. Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 2010;141(7):1146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Coffey EE, Beckel JM, Laties AM, Mitchell CH. Lysosomal alkalization and dysfunction in human fibroblasts with the Alzheimer’s disease-linked presenilin 1 A246E mutation can be reversed with cAMP. Neuroscience. 2014;28(263):111–24.

    Article  CAS  Google Scholar 

  136. 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;24(10):2938–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Perluigi M, Pupo G, Tramutola A, Cini C, Coccia R, Barone E, et al. Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain. Biochim Biophys Acta. 2014;1842(7):1144–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Pei JJ, Hugon J. mTOR-dependent signalling in Alzheimer’s disease. J Cell Mol Med. 2008;12(6b):2525–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Sun YX, Ji XM, Mao XO, Xie L, Jia JP, Galvan V, et al. Differential activation of mTOR complex 1 signaling in human brain with mild to severe Alzheimer’s disease. J Alzheimers Dis. 2014;38(2):437–44.

    Article  CAS  PubMed  Google Scholar 

  140. Tramutola A, Lanzillotta C, Di Domenico F. Targeting mTOR to reduce Alzheimer-related cognitive decline: from current hits to future therapies. Expert Rev Neurother. 2017;17(1):33–45.

    Article  CAS  PubMed  Google Scholar 

  141. Caccamo A, Majumder S, Richardson A, Strong R, Oddo S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and tau effects on cognitive impairments. J Biol Chem. 2010;285(17):13107–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS One. 2010;5(3).

  143. Tramutola A, Lanzillotta C, Barone E, Arena A, Zuliani I, Mosca L, et al. Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome. Transl Neurodegener. 2018;6:7.

    Google Scholar 

  144. Di Domenico F, Tramutola A, Barone E, Lanzillotta C, Defever O, Arena A, et al. Restoration of aberrant mTOR signaling by intranasal rapamycin reduces oxidative damage: focus on HNE-modified proteins in a mouse model of down syndrome. Redox Biol. 2019;9:101162.

    Article  CAS  Google Scholar 

  145. Zhang S, Hedskog L, Petersen CA, Winblad B, Ankarcrona M. Dimebon (latrepirdine) enhances mitochondrial function and protects neuronal cells from death. J Alzheimers Dis. 2010;21(2):389–402.

    Article  CAS  PubMed  Google Scholar 

  146. Lermontova NN, Redkozubov AE, Shevtsova EF, Serkova TP, Kireeva EG, Bachurin SO. Dimebon and tacrine inhibit neurotoxic action of beta-amyloid in culture and block L-type Ca(2+) channels. Bull Exp Biol Med. 2001;132(5):1079–83.

    Article  CAS  PubMed  Google Scholar 

  147. Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, et al. 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. 2008;372(9634):207–15.

    Article  CAS  PubMed  Google Scholar 

  148. Bezprozvanny I. The rise and fall of Dimebon. Drug News Perspect. 2010;23(8):518–23.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Sorrentino V, Romani M, Mouchiroud L, Beck JS, Zhang H, 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 

  150. Cadonic C, Sabbir MG, Albensi BC. Mechanisms of mitochondrial dysfunction in Alzheimer’s disease. Mol Neurobiol. 2016;53(9):6078–90.

    Article  CAS  PubMed  Google Scholar 

  151. Banerjee K, Munshi S, Xu H, Frank DE, Chen HL, Chu CT, et al. Mild mitochondrial metabolic deficits by alpha-ketoglutarate dehydrogenase inhibition cause prominent changes in intracellular autophagic signaling: potential role in the pathobiology of Alzheimer’s disease. Neurochem Int. 2016;96:32–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Vingtdeux V, Chandakkar P, Zhao HT, d’Abramo C, Davies P, Marambaud P. Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-beta peptide degradation. Faseb J. 2011;25(1):219–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Cardoso S, Carvalho C, Correia SC, Seica RM, Moreira PI. Alzheimer’s disease: from mitochondrial perturbations to mitochondrial medicine. Brain Pathol. 2016;26(5):632–47.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46–58.

    Article  PubMed  Google Scholar 

  155. Onyango IG. Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer’s disease. Neural Regener Res. 2018;13(1):19–25.

    Article  Google Scholar 

  156. Di Domenico F, Tramutola A, Barone E, Lanzillotta C, Defever O, Arena A, Zulani I, Foppoli C, Iavarone F, Vincenzoni F, Castagnola M, Butterfield DA, Perluigi M. Restoration of aberrant mTOR signaling by intranasal rapamycin reduces oxidative damage: focus on HNE-modified proteins in a mouse model of Down syndrome. Redox Biol. 2019. https://doi.org/10.1016/j.redox.2019.101162 (in press).

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Biochemical Sciences, Sapienza University of Rome, 00185, Rome, Italy

    Chiara Lanzillotta, Fabio Di Domenico & Marzia Perluigi

  2. Department of Chemistry, University of Kentucky, Lexington, KY, 40506-0055, USA

    D. Allan Butterfield

  3. Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40506-0055, USA

    D. Allan Butterfield

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  1. Chiara Lanzillotta
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  2. Fabio Di Domenico
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  3. Marzia Perluigi
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  4. D. Allan Butterfield
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Correspondence to D. Allan Butterfield.

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This work was supported in part by NIH Grants to DAB [AG060056; AG055596-01A1].

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Lanzillotta, C., Di Domenico, F., Perluigi, M. et al. Targeting Mitochondria in Alzheimer Disease: Rationale and Perspectives. CNS Drugs 33, 957–969 (2019). https://doi.org/10.1007/s40263-019-00658-8

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