BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Mitochondrial dysfunction and Alzheimer's disease: prospects for therapeutic intervention

  • Lim, Ji Woong (Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology) ;
  • Lee, Jiyoun (Department of Global Medical Science, Sungshin University) ;
  • Pae, Ae Nim (Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology)
  • Received : 2019.10.19
  • Published : 2020.01.31
Download PDF
⟨ Previous Next ⟩

Abstract

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease and has become a major socioeconomic issue in many developed countries. Currently available therapeutic agents for AD provide only symptomatic treatments, mainly because the complete mechanism of the AD pathogenesis is still unclear. Although several different hypotheses have been proposed, mitochondrial dysfunction has gathered interest because of its profound effect on brain bioenergetics and neuronal survival in the pathophysiology of AD. Various therapeutic agents targeting the mitochondrial pathways associated with AD have been developed over the past decade. Although most of these agents are still early in the clinical development process, they are used to restore mitochondrial function, which provides an alternative therapeutic strategy that is likely to slow the progression of the disease. In this mini review, we will survey the AD-related mitochondrial pathways and their small-molecule modulators that have therapeutic potential. We will focus on recently reported examples, and also overview the current challenges and future perspectives of ongoing research.

Keywords

References

  1. Anand R, Gill KD and Mahdi AA (2014) Therapeutics of Alzheimer's disease: Past, present and future. Neuropharmacology 76 Pt A, 27-50 https://doi.org/10.1016/j.neuropharm.2013.07.004
  2. Perry G, Nunomura A, Hirai K, Takeda A, Aliev G and Smith MA (2000) Oxidative damage in Alzheimer's disease: the metabolic dimension. Int J Dev Neurosci 18, 417-421 https://doi.org/10.1016/S0736-5748(00)00006-X
  3. Schmitt K, Grimm A, Kazmierczak A, Strosznajder JB, Gotz J and Eckert A (2012) Insights into mitochondrial dysfunction: aging, amyloid-beta, and tau-A deleterious trio. Antioxid Redox Signal 16, 1456-1466 https://doi.org/10.1089/ars.2011.4400
  4. Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT and Brinton RD (2009) Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 106, 14670-14675 https://doi.org/10.1073/pnas.0903563106
  5. Swerdlow RH, Burns JM and Khan SM (2010) The Alzheimer's disease mitochondrial cascade hypothesis. J Alzheimers Dis 20 Suppl 2, S265-279
  6. Hauptmann S, Scherping I, Drose S et al (2009) Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging 30, 1574-1586 https://doi.org/10.1016/j.neurobiolaging.2007.12.005
  7. Shulman RG, Rothman DL, Behar KL and Hyder F (2004) Energetic basis of brain activity: implications for neuroimaging. Trends Neurosci 27, 489-495 https://doi.org/10.1016/j.tins.2004.06.005
  8. Mao P and Reddy PH (2011) Aging and amyloid beta-induced oxidative DNA damage and mitochondrial dysfunction in Alzheimer's disease: implications for early intervention and therapeutics. Biochim Biophys Acta 1812, 1359-1370 https://doi.org/10.1016/j.bbadis.2011.08.005
  9. Keil U, Bonert A, Marques CA et al (2004) Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem 279, 50310-50320 https://doi.org/10.1074/jbc.M405600200
  10. Eckert GP, Renner K, Eckert SH et al (2012) Mitochondrial dysfunction-a pharmacological target in Alzheimer's disease. Mol Neurobiol 46, 136-150 https://doi.org/10.1007/s12035-012-8271-z
  11. Johri A and Beal MF (2012) Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther 342, 619-630 https://doi.org/10.1124/jpet.112.192138
  12. Moreira PI, Carvalho C, Zhu X, Smith MA and Perry G (2010) Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology. Biochim Biophys Acta 1802, 2-10 https://doi.org/10.1016/j.bbadis.2009.10.006
  13. Muller WE, Eckert A, Kurz C, Eckert GP and Leuner K (2010) Mitochondrial dysfunction: common final pathway in brain aging and Alzheimer's disease-therapeutic aspects. Mol Neurobiol 41, 159-171 https://doi.org/10.1007/s12035-010-8141-5
  14. Swerdlow RH, Burns JM and Khan SM (2014) The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives. Biochim Biophys Acta 1842, 1219-1231 https://doi.org/10.1016/j.bbadis.2013.09.010
  15. Farlow MR, Miller ML and Pejovic V (2008) Treatment options in Alzheimer's disease: maximizing benefit, managing expectations. Dement Geriatr Cogn Disord 25, 408-422 https://doi.org/10.1159/000122962
  16. Moehle EA, Shen K and Dillin A (2019) Mitochondrial proteostasis in the context of cellular and organismal health and aging. J Biol Chem 294, 5396-5407 https://doi.org/10.1074/jbc.tm117.000893
  17. Tatsuta T and Langer T (2008) Quality control of mitochondria: protection against neurodegeneration and ageing. EMBO J 27, 306-314 https://doi.org/10.1038/sj.emboj.7601972
  18. Franco-Iborra S, Vila M and Perier C (2018) Mitochondrial Quality Control in Neurodegenerative Diseases: Focus on Parkinson's Disease and Huntington's Disease. Front Neurosci 12, 342 https://doi.org/10.3389/fnins.2018.00342
  19. Tilokani L, Nagashima S, Paupe V and Prudent J (2018) Mitochondrial dynamics: overview of molecular mechanisms. Essays Biochem 62, 341-360 https://doi.org/10.1042/EBC20170104
  20. Burte F, Carelli V, Chinnery PF and Yu-Wai-Man P (2015) Disturbed mitochondrial dynamics and neurodegenerative disorders. Nat Rev Neurol 11, 11-24 https://doi.org/10.1038/nrneurol.2014.228
  21. Kandimalla R and Reddy PH (2016) Multiple faces of dynamin-related protein 1 and its role in Alzheimer's disease pathogenesis. Biochim Biophys Acta 1862, 814-828 https://doi.org/10.1016/j.bbadis.2015.12.018
  22. Reddy PH and Beal MF (2008) Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med 14, 45-53 https://doi.org/10.1016/j.molmed.2007.12.002
  23. Manczak M and Reddy PH (2012) Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage. Hum Mol Genet 21, 2538-2547 https://doi.org/10.1093/hmg/dds072
  24. Silva DF, Selfridge JE, Lu J et al (2013) Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines. Hum Mol Genet 22, 3931-3946 https://doi.org/10.1093/hmg/ddt247
  25. Calkins MJ, Manczak M, Mao P, Shirendeb U and Reddy PH (2011) 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 20, 4515-4529 https://doi.org/10.1093/hmg/ddr381
  26. Manczak M, Calkins MJ and Reddy PH (2011) Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage. Hum Mol Genet 20, 2495-2509 https://doi.org/10.1093/hmg/ddr139
  27. Cassidy-Stone A, Chipuk JE, Ingerman E et al (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 14, 193-204 https://doi.org/10.1016/j.devcel.2007.11.019
  28. Wang W, Yin J, Ma X et al (2017) Inhibition of mitochondrial fragmentation protects against Alzheimer's disease in rodent model. Hum Mol Genet 26, 4118-4131 https://doi.org/10.1093/hmg/ddx299
  29. Baek SH, Park SJ, Jeong JI et al (2017) Inhibition of Drp1 Ameliorates Synaptic Depression, Abeta Deposition, and Cognitive Impairment in an Alzheimer's Disease Model. J Neurosci 37, 5099-5110 https://doi.org/10.1523/JNEUROSCI.2385-16.2017
  30. Guo X, Disatnik MH, Monbureau M, Shamloo M, Mochly-Rosen D and Qi X (2013) Inhibition of mitochondrial fragmentation diminishes Huntington's disease-associated neurodegeneration. J Clin Invest 123, 5371-5388 https://doi.org/10.1172/JCI70911
  31. Qi X, Qvit N, Su YC and Mochly-Rosen D (2013) A novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity. J Cell Sci 126, 789-802 https://doi.org/10.1242/jcs.114439
  32. Numadate A, Mita Y, Matsumoto Y, Fujii S and Hashimoto Y (2014) Development of 2-thioxoquinazoline-4-one derivatives as dual and selective inhibitors of dynaminrelated protein 1 (Drp1) and puromycin-sensitive aminopeptidase (PSA). Chem Pharm Bull (Tokyo) 62, 979-988 https://doi.org/10.1248/cpb.c14-00333
  33. Mallat A, Uchiyama LF, Lewis SC et al (2018) Discovery and characterization of selective small molecule inhibitors of the mammalian mitochondrial division dynamin, DRP1. Biochem Biophys Res Commun 499, 556-562 https://doi.org/10.1016/j.bbrc.2018.03.189
  34. Kuruva CS, Manczak M, Yin X, Ogunmokun G, Reddy AP and Reddy PH (2017) Aqua-soluble DDQ reduces the levels of Drp1 and Abeta and inhibits abnormal interactions between Abeta and Drp1 and protects Alzheimer's disease neurons from Abeta- and Drp1-induced mitochondrial and synaptic toxicities. Hum Mol Genet 26, 3375-3395 https://doi.org/10.1093/hmg/ddx226
  35. Smith G and Gallo G (2017) To mdivi-1 or not to mdivi-1: Is that the question? Dev Neurobiol 77, 1260-1268 https://doi.org/10.1002/dneu.22519
  36. Valente EM, Abou-Sleiman PM, Caputo V et al (2004) Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158-1160 https://doi.org/10.1126/science.1096284
  37. Pickrell AM and Youle RJ (2015) The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease. Neuron 85, 257-273 https://doi.org/10.1016/j.neuron.2014.12.007
  38. Du F, Yu Q, Yan S et al (2017) PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer's disease. Brain 140, 3233-3251 https://doi.org/10.1093/brain/awx258
  39. Fang EF, Hou Y, Palikaras K et al (2019) Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer's disease. Nat Neurosci 22, 401-412 https://doi.org/10.1038/s41593-018-0332-9
  40. Andreux PA, Blanco-Bose W, Ryu D et al (2019) The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat Metab 1, 595 https://doi.org/10.1038/s42255-019-0073-4
  41. Lambourne OA and Mehellou Y (2018) Chemical Strategies for Activating PINK1, a Protein Kinase Mutated in Parkinson's Disease. Chembiochem 19, 2433-2437 https://doi.org/10.1002/cbic.201800497
  42. Hertz NT, Berthet A, Sos ML et al (2013) A neo-substrate that amplifies catalytic activity of parkinson's-diseaserelated kinase PINK1. Cell 154, 737-747 https://doi.org/10.1016/j.cell.2013.07.030
  43. Osgerby L, Lai YC, Thornton PJ et al (2017) Kinetin Riboside and Its ProTides Activate the Parkinson's Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial Depolarization. J Med Chem 60, 3518-3524 https://doi.org/10.1021/acs.jmedchem.6b01897
  44. Barini E, Miccoli A, Tinarelli F et al (2018) The Anthelmintic Drug Niclosamide and Its Analogues Activate the Parkinson's Disease Associated Protein Kinase PINK1. Chembiochem 19, 425-429 https://doi.org/10.1002/cbic.201700500
  45. Halestrap AP (2009) What is the mitochondrial permeability transition pore? J Mol Cell Cardiol 46, 821-831 https://doi.org/10.1016/j.yjmcc.2009.02.021
  46. Baines CP, Kaiser RA, Purcell NH et al (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434, 658-662 https://doi.org/10.1038/nature03434
  47. Du H, Guo L, Fang F et al (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nat Med 14, 1097-1105 https://doi.org/10.1038/nm.1868
  48. Du H, Guo L, Zhang W, Rydzewska M and Yan S (2011) Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model. Neurobiol Aging 32, 398-406 https://doi.org/10.1016/j.neurobiolaging.2009.03.003
  49. Briston T, Selwood DL, Szabadkai G and Duchen MR (2019) Mitochondrial Permeability Transition: A Molecular Lesion with Multiple Drug Targets. Trends Pharmacol Sci 40, 50-70 https://doi.org/10.1016/j.tips.2018.11.004
  50. Elkamhawy A, Lee J, Park BG, Park I, Pae AN and Roh EJ (2014) Novel quinazoline-urea analogues as modulators for Abeta-induced mitochondrial dysfunction: design, synthesis, and molecular docking study. Eur J Med Chem 84, 466-475 https://doi.org/10.1016/j.ejmech.2014.07.027
  51. Valasani KR, Sun Q, Fang D et al (2016) Identification of a Small Molecule Cyclophilin D Inhibitor for Rescuing Abeta-Mediated Mitochondrial Dysfunction. ACS Med Chem Lett 7, 294-299 https://doi.org/10.1021/acsmedchemlett.5b00451
  52. Valasani KR, Vangavaragu JR, Day VW and Yan SS (2014) Structure based design, synthesis, pharmacophore modeling, virtual screening, and molecular docking studies for identification of novel cyclophilin D inhibitors. J Chem Inf Model 54, 902-912 https://doi.org/10.1021/ci5000196
  53. Park I, Londhe AM, Lim JW et al (2017) Discovery of non-peptidic small molecule inhibitors of cyclophilin D as neuroprotective agents in Abeta-induced mitochondrial dysfunction. J Comput Aided Mol Des 31, 929-941 https://doi.org/10.1007/s10822-017-0067-9
  54. Paul SM and Purdy RH (1992) Neuroactive steroids. FASEB J 6, 2311-2322 https://doi.org/10.1096/fasebj.6.6.1347506
  55. Porcu P, Barron AM, Frye CA et al (2016) Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research. J Neuroendocrinol 28, 12351
  56. Rupprecht R, Papadopoulos V, Rammes G et al (2010) Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov 9, 971-988 https://doi.org/10.1038/nrd3295
  57. Banati RB, Middleton RJ, Chan R et al (2014) Positron emission tomography and functional characterization of a complete PBR/TSPO knockout. Nat Commun 5, 5452 https://doi.org/10.1038/ncomms6452
  58. Li J, Wang J and Zeng Y (2007) Peripheral benzodiazepine receptor ligand, PK11195 induces mitochondria cytochrome c release and dissipation of mitochondria potential via induction of mitochondria permeability transition. Eur J Pharmacol 560, 117-122 https://doi.org/10.1016/j.ejphar.2006.12.027
  59. Sileikyte J, Blachly-Dyson E, Sewell R et al (2014) Regulation of the mitochondrial permeability transition pore by the outer membrane does not involve the peripheral benzodiazepine receptor (Translocator Protein of 18 kDa (TSPO)). J Biol Chem 289, 13769-13781 https://doi.org/10.1074/jbc.M114.549634
  60. Selvaraj V and Stocco DM (2015) The changing landscape in translocator protein (TSPO) function. Trends Endocrinol Metab 26, 341-348 https://doi.org/10.1016/j.tem.2015.02.007
  61. Barron AM, Garcia-Segura LM, Caruso D et al (2013) Ligand for translocator protein reverses pathology in a mouse model of Alzheimer's disease. J Neurosci 33, 8891-8897 https://doi.org/10.1523/JNEUROSCI.1350-13.2013
  62. Kim T, Yang HY, Park BG et al (2017) Discovery of benzimidazole derivatives as modulators of mitochondrial function: A potential treatment for Alzheimer's disease. Eur J Med Chem 125, 1172-1192 https://doi.org/10.1016/j.ejmech.2016.11.017
  63. Monga S, Nagler R, Amara R, Weizman A and Gavish M (2019) Inhibitory Effects of the Two Novel TSPO Ligands 2-Cl-MGV-1 and MGV-1 on LPS-induced Microglial Activation. Cells 8, 486 https://doi.org/10.3390/cells8050486
  64. Yang SY, He XY and Miller D (2011) Hydroxysteroid (17beta) dehydrogenase X in human health and disease. Mol Cell Endocrinol 343, 1-6 https://doi.org/10.1016/j.mce.2011.06.011
  65. Yang SY, He XY, Isaacs C, Dobkin C, Miller D and Philipp M (2014) Roles of 17beta-hydroxysteroid dehydrogenase type 10 in neurodegenerative disorders. J Steroid Biochem Mol Biol 143, 460-472 https://doi.org/10.1016/j.jsbmb.2014.07.001
  66. He XY, Wegiel J and Yang SY (2005) Intracellular oxidation of allopregnanolone by human brain type 10 17beta-hydroxysteroid dehydrogenase. Brain Res 1040, 29-35 https://doi.org/10.1016/j.brainres.2005.01.022
  67. Lustbader JW, Cirilli M, Lin C et al (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science 304, 448-452 https://doi.org/10.1126/science.1091230
  68. Morsy A and Trippier PC (2019) Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors for the Treatment of Alzheimer's Disease. J Med Chem 62, 4252-4264 https://doi.org/10.1021/acs.jmedchem.8b01530
  69. Boutin S, Roy J, Maltais R, Alata W, Calon F and Poirier D (2018) Identification of steroidal derivatives inhibiting the transformations of allopregnanolone and estradiol by 17beta-hydroxysteroid dehydrogenase type 10. Bioorg Med Chem Lett 28, 3554-3559 https://doi.org/10.1016/j.bmcl.2018.09.031
  70. Lim YA, Grimm A, Giese M et al (2011) Inhibition of the mitochondrial enzyme ABAD restores the amyloid-betamediated deregulation of estradiol. PLoS One 6, e28887 https://doi.org/10.1371/journal.pone.0028887
  71. Valasani KR, Hu G, Chaney MO and Yan SS (2013) Structure-based design and synthesis of benzothiazole phosphonate analogues with inhibitors of human ABAD-Abeta for treatment of Alzheimer's disease. Chem Biol Drug Des 81, 238-249 https://doi.org/10.1111/cbdd.12068
  72. Benek O, Hroch L, Aitken L et al (2017) 6-benzothiazolyl ureas, thioureas and guanidines are potent inhibitors of ABAD/17beta-HSD10 and potential drugs for Alzheimer's disease treatment: Design, synthesis and in vitro evaluation. Med Chem 13, 345-358 https://doi.org/10.2174/1573406413666170109142725
  73. Viswanath ANI, Kim T, Jung SY, Lim SM and Pae AN (2017) In silico-designed novel non-peptidic ABAD LD hot spot mimetics reverse Abeta-induced mitochondrial impairments in vitro. Chem Biol Drug Des 90, 1041-1055 https://doi.org/10.1111/cbdd.13065
  74. Holmstrom KM and Finkel T (2014) Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol 15, 411-421 https://doi.org/10.1038/nrm3801
  75. Tonnies E and Trushina E (2017) Oxidative Stress, Synaptic Dysfunction, and Alzheimer's Disease. J Alzheimers Dis 57, 1105-1121 https://doi.org/10.3233/JAD-161088
  76. Cheignon C, Tomas M, Bonnefont-Rousselot D, Faller P, Hureau C and Collin F (2018) Oxidative stress and the amyloid beta peptide in Alzheimer's disease. Redox Biol 14, 450-464 https://doi.org/10.1016/j.redox.2017.10.014
  77. Barnham KJ and Bush AI (2014) Biological metals and metal-targeting compounds in major neurodegenerative diseases. Chem Soc Rev 43, 6727-6749 https://doi.org/10.1039/C4CS00138A
  78. Dumont M, Kipiani K, Yu F et al (2011) Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer's disease. J Alzheimers Dis 27, 211-223 https://doi.org/10.3233/JAD-2011-110209
  79. Gugliandolo A, Bramanti P and Mazzon E (2017) Role of Vitamin E in the Treatment of Alzheimer's Disease: Evidence from Animal Models. Int J Mol Sci 18, 2504 https://doi.org/10.3390/ijms18122504
  80. McManus MJ, Murphy MP and 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, 15703-15715 https://doi.org/10.1523/JNEUROSCI.0552-11.2011
  81. Covey MV, Murphy MP, Hobbs CE, Smith RA and Oorschot DE (2006) Effect of the mitochondrial antioxidant, Mito Vitamin E, on hypoxic-ischemic striatal injury in neonatal rats: a dose-response and stereological study. Exp Neurol 199, 513-519 https://doi.org/10.1016/j.expneurol.2005.12.026
  82. Webb M, Sideris DP and Biddle M (2019) Modulation of mitochondrial dysfunction for treatment of disease. Bioorg Med Chem Lett 29, 1270-1277 https://doi.org/10.1016/j.bmcl.2019.03.041
  83. Oliver DMA and Reddy PH (2019) Small molecules as therapeutic drugs for Alzheimer's disease. Mol Cell Neurosci 96, 47-62 https://doi.org/10.1016/j.mcn.2019.03.001
  84. El-Hattab AW, Zarante AM, Almannai M and Scaglia F (2017) Therapies for mitochondrial diseases and current clinical trials. Mol Genet Metab 122, 1-9