BMB Reports

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

DOI QR Code

Emerging perspectives on mitochondrial dysfunction and inflammation in Alzheimer's disease

  • Yoo, Seung-Min (School of Biological Sciences, Seoul National University) ;
  • Park, Jisu (School of Biological Sciences, Seoul National University) ;
  • Kim, Seo-Hyun (School of Biological Sciences, Seoul National University) ;
  • Jung, Yong-Keun (School of Biological Sciences, Seoul National University)
  • Received : 2019.10.28
  • Published : 2020.01.31
Download PDF
⟨ Previous Next ⟩

Abstract

Despite enduring diverse insults, mitochondria maintain normal functions through mitochondrial quality control. However, the failure of mitochondrial quality control resulting from excess damage and mechanical defects causes mitochondrial dysfunction, leading to various human diseases. Recent studies have reported that mitochondrial defects are found in Alzheimer's disease (AD) and worsen AD symptoms. In AD pathogenesis, mitochondrial dysfunction-driven generation of reactive oxygen species (ROS) and their contribution to neuronal damage has been widely studied. In contrast, studies on mitochondrial dysfunction-associated inflammatory responses have been relatively scarce. Moreover, ROS produced upon failure of mitochondrial quality control may be linked to the inflammatory response and influence the progression of AD. Thus, this review will focus on inflammatory pathways that are associated with and initiated through defective mitochondria and will summarize recent progress on the role of mitochondria-mediated inflammation in AD. We will also discuss how reducing mitochondrial dysfunction-mediated inflammation could affect AD.

Keywords

References

  1. Smith RA, Hartley RC, Cocheme HM and Murphy MP (2012) Mitochondrial pharmacology. Trends Pharmacol Sci 33, 341-352 https://doi.org/10.1016/j.tips.2012.03.010
  2. Yoo SM and Jung YK (2018) A Molecular Approach to Mitophagy and Mitochondrial Dynamics. Mol Cells 41, 18-26 https://doi.org/10.14348/MOLCELLS.2018.2277
  3. Suomalainen A and Battersby BJ (2018) Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat Rev Mol Cell Biol 19, 77-92 https://doi.org/10.1038/nrm.2017.66
  4. Leyns CEG, Ulrich JD, Finn MB et al (2017) TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci U S A 114, 11524-11529 https://doi.org/10.1073/pnas.1710311114
  5. Corder EH, Saunders AM, Strittmatter WJ et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921-923 https://doi.org/10.1126/science.8346443
  6. Robert J, Button EB, Yuen B et al (2017) Clearance of beta-amyloid is facilitated by apolipoprotein E and circulating high-density lipoproteins in bioengineered human vessels. Elife 6, e29595. https://doi.org/10.7554/elife.29595
  7. Tai LM, Ghura S, Koster KP et al (2015) APOE-modulated Abeta-induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective. J Neurochem 133, 465-488 https://doi.org/10.1111/jnc.13072
  8. Zhang B, Gaiteri C, Bodea LG et al (2013) Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer's Disease. Cell 153, 707-720 https://doi.org/10.1016/j.cell.2013.03.030
  9. Griffin WS, Stanley LC, Ling C et al (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A 86, 7611-7615 https://doi.org/10.1073/pnas.86.19.7611
  10. Eikelenboom P and Stam FC (1982) Immunoglobulins and complement factors in senile plaques. An immunoperoxidase study. Acta Neuropathol 57, 239-242 https://doi.org/10.1007/BF00685397
  11. Eriksen JL, Sagi SA, Smith TE et al (2003) NSAIDs and enantiomers of flurbiprofen target ${\gamma}$-secretase and lower $A{\beta}42$ in vivo. J Clin Invest 112, 440-449 https://doi.org/10.1172/JCI18162
  12. Yan Q, Zhang J, Liu H et al (2003) Anti-Inflammatory Drug Therapy Alters ${\beta}$-Amyloid Processing and Deposition in an Animal Model of Alzheimer's Disease. J Neurosci 23, 7504-7509 https://doi.org/10.1523/JNEUROSCI.23-20-07504.2003
  13. Zandi PP, Anthony JC, Hayden KM, Mehta K, Mayer L and Breitner JCS (2002) Reduced incidence of AD with NSAID but not not H2 receptor antagonists: the Cache County Study. Neurology 59, 880-886 https://doi.org/10.1212/WNL.59.6.880
  14. Breitner JC, Welsh KA, Helms MJ et al (1995) Delayed onset of Alzheimer's disease with nonsteroidal antiinflammatory and histamine H2 blocking drugs. Neurobiol Aging 16, 523-530 https://doi.org/10.1016/0197-4580(95)00049-K
  15. Wyss-Coray T, Lin C, Yan F et al (2001) TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med 7, 612-618 https://doi.org/10.1038/87945
  16. Wyss-Coray T, Yan F, Lin AHT et al (2002) Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc Natl Acad Sci U S A 99, 10837-10842 https://doi.org/10.1073/pnas.162350199
  17. Liu CC, Hu J, Zhao N et al (2017) Astrocytic LRP1 Mediates Brain Abeta Clearance and Impacts Amyloid Deposition. J Neurosci 37, 4023-4031 https://doi.org/10.1523/JNEUROSCI.3442-16.2017
  18. Kanekiyo T, Cirrito JR, Liu CC et al (2013) Neuronal clearance of amyloid-beta by endocytic receptor LRP1. J Neurosci 33, 19276-19283 https://doi.org/10.1523/JNEUROSCI.3487-13.2013
  19. Fu Y, Hsiao JH, Paxinos G, Halliday GM and Kim WS (2016) ABCA7 Mediates Phagocytic Clearance of Amyloid-beta in the Brain. J Alzheimers Dis 54, 569-584 https://doi.org/10.3233/JAD-160456
  20. Chakrabarty P, Li A, Ceballos-Diaz C et al (2015) IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 85, 519-533 https://doi.org/10.1016/j.neuron.2014.11.020
  21. Grilli M, Ribola M, Alberici A, Valerio A, Memo M and Spano P (1995) Identification and characterization of a kappa B/Rel binding site in the regulatory region of the amyloid precursor protein gene. J Biol Chem 270, 26774-26777 https://doi.org/10.1074/jbc.270.45.26774
  22. Cho HJ, Kim SK, Jin SM et al (2007) IFN-gamma-induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes. Glia 55, 253-262 https://doi.org/10.1002/glia.20451
  23. Sy M, Kitazawa M, Medeiros R et al (2011) Inflammation induced by infection potentiates tau pathological features in transgenic mice. Am J Pathol 178, 2811-2822 https://doi.org/10.1016/j.ajpath.2011.02.012
  24. Billups B and Forsythe ID (2002) Presynaptic Mitochondrial Calcium Sequestration Influences Transmission at Mammalian Central Synapses. J Neurosci 22, 5840-5847 https://doi.org/10.1523/jneurosci.22-14-05840.2002
  25. Zhou B, Yu P, Lin M-Y, Sun T, Chen Y and Sheng ZH (2016) Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits. J Cell Biol 214, 103-119 https://doi.org/10.1083/jcb.201605101
  26. Tang FL, Liu W, Hu JX et al (2015) VPS35 Deficiency or Mutation Causes Dopaminergic Neuronal Loss by Impairing Mitochondrial Fusion and Function. Cell Rep 12, 1631-1643 https://doi.org/10.1016/j.celrep.2015.08.001
  27. Johnson AB and Blum NR (1970) Nucleoside phosphatase activities associated with the tangles and plaques of alzheimer's disease: a histochemical study of natural and experimental neurofibrillary tangles. J Neuropathol Exp Neurol 29, 463-478 https://doi.org/10.1097/00005072-197007000-00009
  28. Zhang L, Trushin S, Christensen TA et al (2016) Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease. Sci Rep 6, 18725 https://doi.org/10.1038/srep18725
  29. Gibson GE, Sheu KF, Blass JP et al (1988) Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer's disease. Arch Neurol 45, 836-840 https://doi.org/10.1001/archneur.1988.00520320022009
  30. Sorbi S, Bird ED and Blass JP (1983) Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain. Ann Neurol 13, 72-78 https://doi.org/10.1002/ana.410130116
  31. Mutisya EM, Bowling AC and Beal MF (1994) Cortical Cytochrome Oxidase Activity Is Reduced in Alzheimer's Disease. J Neurochem 63, 2179-2184 https://doi.org/10.1046/j.1471-4159.1994.63062179.x
  32. Mecocci P, MacGarvey U and Beal MF (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann Neurol 36, 747-751 https://doi.org/10.1002/ana.410360510
  33. Reddy PH, Yin X, Manczak M et al (2018) Mutant APP and amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer's disease. Hum Mol Genet 27, 2502-2516 https://doi.org/10.1093/hmg/ddy154
  34. Devi L, Prabhu BM, Galati DF, Avadhani NG and Anandatheerthavarada HK (2006) Accumulation of Amyloid Precursor Protein in the Mitochondrial Import Channels of Human Alzheimer's Disease Brain Is Associated with Mitochondrial Dysfunction. J Neurosci 26, 9057-9068 https://doi.org/10.1523/JNEUROSCI.1469-06.2006
  35. Lustbader JW, Cirilli M, Lin C et al (2004) ABAD Directly Links $A{\beta}$ to Mitochondrial Toxicity in Alzheimer's Disease. Science 304, 448-452 https://doi.org/10.1126/science.1091230
  36. Manczak M and Reddy PH (2012) Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer's disease. Hum Mol Genet 21, 5131-5146 https://doi.org/10.1093/hmg/dds360
  37. Park J, Choi H, Min JS et al (2015) Loss of mitofusin 2 links beta-amyloid-mediated mitochondrial fragmentation and Cdk5-induced oxidative stress in neuron cells. J Neurochem 132, 687-702 https://doi.org/10.1111/jnc.12984
  38. Kim DI, Lee KH, Gabr AA et al (2016) $A{\beta}$-Induced Drp1 phosphorylation through Akt activation promotes excessive mitochondrial fission leading to neuronal apoptosis. Biochim Biophys Acta 1863, 2820-2834 https://doi.org/10.1016/j.bbamcr.2016.09.003
  39. Fukui H, Diaz F, Garcia S and Moraes CT (2007) Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 104, 14163-14168 https://doi.org/10.1073/pnas.0705738104
  40. Krishnan KJ, Ratnaike TE, De Gruyter HLM, Jaros E and Turnbull DM (2012) Mitochondrial DNA deletions cause the biochemical defect observed in Alzheimer's disease. Neurobiol Aging 33, 2210-2214 https://doi.org/10.1016/j.neurobiolaging.2011.08.009
  41. Hoekstra JG, Hipp MJ, Montine TJ and Kennedy SR (2016) Mitochondrial DNA mutations increase in early stage Alzheimer disease and are inconsistent with oxidative damage. Ann Neurol 80, 301-306 https://doi.org/10.1002/ana.24709
  42. Coskun PE, Beal MF and Wallace DC (2004) Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci U S A 101, 10726-10731 https://doi.org/10.1073/pnas.0403649101
  43. Hoglinger GU, Lannuzel A, Khondiker ME et al (2005) The mitochondrial complex I inhibitor rotenone triggers a cerebral tauopathy. J Neurochem 95, 930-939 https://doi.org/10.1111/j.1471-4159.2005.03493.x
  44. Lopez-Otin C, Blasco MA, Partridge L, Serrano M and Kroemer G (2013) The hallmarks of aging. Cell 153, 1194-1217 https://doi.org/10.1016/j.cell.2013.05.039
  45. Scheibye-Knudsen M, Fang EF, Croteau DL, Wilson DM and Bohr VA (2015) Protecting the mitochondrial powerhouse. Trends Cell Biol 25, 158-170 https://doi.org/10.1016/j.tcb.2014.11.002
  46. Hammerling BC and Gustafsson AB (2014) Mitochondrial quality control in the myocardium: Cooperation between protein degradation and mitophagy. J Mol Cell Cardiol 75, 122-130 https://doi.org/10.1016/j.yjmcc.2014.07.013
  47. Cenini G and Voos W (2016) Role of Mitochondrial Protein Quality Control in Oxidative Stress-induced Neurodegenerative Diseases. Curr Alzheimer Res 13, 164-173 https://doi.org/10.2174/1567205012666150921103213
  48. Bragoszewski P, Turek M and Chacinska A (2017) Control of mitochondrial biogenesis and function by the ubiquitin - proteasome system. Open Biol 7, 17007
  49. Suliman HB and Piantadosi CA (2016) Mitochondrial Quality Control as a Therapeutic Target. Pharmacol Rev 68, 20-48 https://doi.org/10.1124/pr.115.011502
  50. Meyer A, Laverny G, Bernardi L et al (2018) Mitochondria: An Organelle of Bacterial Origin Controlling Inflammation. Front Immunol 9, 536 https://doi.org/10.3389/fimmu.2018.00536
  51. Archibald JM (2015) Endosymbiosis and Eukaryotic Cell Evolution. Curr Biol 25, R911-921 https://doi.org/10.1016/j.cub.2015.07.055
  52. Barbalat R, Ewald SE, Mouchess ML and Barton GM (2011) Nucleic acid recognition by the innate immune system. Annu Rev Immunol 29, 185-214 https://doi.org/10.1146/annurev-immunol-031210-101340
  53. Contis A, Mitrovic S, Lavie J et al (2017) Neutrophil-derived mitochondrial DNA promotes receptor activator of nuclear factor kappaB and its ligand signalling in rheumatoid arthritis. Rheumatology 56, 1200-1205 https://doi.org/10.1093/rheumatology/kex041
  54. Shimada K, Crother TR, Karlin J et al (2012) Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401-414 https://doi.org/10.1016/j.immuni.2012.01.009
  55. Bai J and Liu F (2019) The cGAS-cGAMP-STING Pathway: A Molecular Link Between Immunity and Metabolism. Diabetes 68, 1099-1108 https://doi.org/10.2337/dbi18-0052
  56. Dorward DA, Lucas CD, Chapman GB, Haslett C, Dhaliwal K and Rossi AG (2015) The role of formylated peptides and formyl peptide receptor 1 in governing neutrophil function during acute inflammation. Am J Pathol 185, 1172-1184 https://doi.org/10.1016/j.ajpath.2015.01.020
  57. Dahlgren C, Gabl M, Holdfeldt A, Winther M and Forsman H (2016) Basic characteristics of the neutrophil receptors that recognize formylated peptides, a dangerassociated molecular pattern generated by bacteria and mitochondria. Biochem Pharmacol 114, 22-39 https://doi.org/10.1016/j.bcp.2016.04.014
  58. Raoof M, Zhang Q, Itagaki K and Hauser CJ (2010) Mitochondrial peptides are potent immune activators that activate human neutrophils via FPR-1. J Trauma 68, 1328-1332; discussion 1332-1324 https://doi.org/10.1097/TA.0b013e3181dcd28d
  59. Pan ZK, Chen LY, Cochrane CG and Zuraw BL (2000) fMet-Leu-Phe stimulates proinflammatory cytokine gene expression in human peripheral blood monocytes: the role of phosphatidylinositol 3-kinase. J Immunol 164, 404-411 https://doi.org/10.4049/jimmunol.164.1.404
  60. Banoth B and Cassel SL (2018) Mitochondria in innate immune signaling. Transl Res 202, 52-68 https://doi.org/10.1016/j.trsl.2018.07.014
  61. Iyer SS, He Q, Janczy JR et al (2013) Mitochondrial Cardiolipin Is Required for Nlrp3 Inflammasome Activation. Immunity 39, 311-323 https://doi.org/10.1016/j.immuni.2013.08.001
  62. Chu CT, Bayir H and Kagan VE (2014) LC3 binds externalized cardiolipin on injured mitochondria to signal mitophagy in neurons Implications for Parkinson disease. Autophagy 10, 376-378 https://doi.org/10.4161/auto.27191
  63. Allard B, Longhi MS, Robson SC and Stagg J (2017) The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets. Immunol Rev 276, 121-144 https://doi.org/10.1111/imr.12528
  64. Amores-Iniesta J, Barbera-Cremades M, Martinez CM et al (2017) Extracellular ATP Activates the NLRP3 Inflammasome and Is an Early Danger Signal of Skin Allograft Rejection. Cell Rep 21, 3414-3426 https://doi.org/10.1016/j.celrep.2017.11.079
  65. Cauwels A, Rogge E, Vandendriessche B, Shiva S and Brouckaert P (2014) Extracellular ATP drives systemic inflammation, tissue damage and mortality. Cell Death Dis 5, e1102-e1102
  66. Eleftheriadis T, Pissas G, Liakopoulos V and Stefanidis I (2016) Cytochrome c as a Potentially Clinical Useful Marker of Mitochondrial and Cellular Damage. Front Immunol 7, 279 https://doi.org/10.3389/fimmu.2016.00279
  67. Lin ML, Zhan Y, Projetto AI et al (2008) Selective suicide of cross-presenting CD8(+) dendritic cells by cytochrome c injection shows functional heterogeneity within this subset. Proc Natl Acad Sci U S A 105, 3029-3034 https://doi.org/10.1073/pnas.0712394105
  68. Codina R, Vanasse A, Kelekar A, Vezys V and Jemmerson R (2010) Cytochrome c-induced lymphocyte death from the outside in: inhibition by serum leucine-rich alpha-2-glycoprotein-1. Apoptosis 15, 139-152 https://doi.org/10.1007/s10495-009-0412-0
  69. Pullerits R, Bokarewa M, Jonsson IM, Verdrengh M and Tarkowski A (2005) Extracellular cytochrome c, a mitochondrial apoptosis-related protein, induces arthritis. Rheumatology 44, 32-39 https://doi.org/10.1093/rheumatology/keh406
  70. Mittal M, Siddiqui MR, Tran K, Reddy SP and Malik AB (2014) Reactive Oxygen Species in Inflammation and Tissue Injury. Antioxid Redox Sign 20, 1126-1167 https://doi.org/10.1089/ars.2012.5149
  71. Kozlov AV, Lancaster JR, Meszaros AT and Weidinger A (2017) Mitochondria-meditated pathways of organ failure upon inflammation. Redox Biol 13, 170-181 https://doi.org/10.1016/j.redox.2017.05.017
  72. Naik E and Dixit VM (2011) Mitochondrial reactive oxygen species drive proinflammatory cytokine production. J Exp Med 208, 417-420 https://doi.org/10.1084/jem.20110367
  73. Nakahira K, Haspel JA, Rathinam VAK et al (2011) Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12, 222-230 https://doi.org/10.1038/ni.1980
  74. West AP, Khoury-Hanold W, Staron M et al (2015) Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553-557 https://doi.org/10.1038/nature14156
  75. Tian J, Avalos AM, Mao SY et al (2007) Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol 8, 487-496 https://doi.org/10.1038/ni1457
  76. Julian MW, Shao GH, Bao SY et al (2012) Mitochondrial Transcription Factor A Serves as a Danger Signal by Augmenting Plasmacytoid Dendritic Cell Responses to DNA. J Immunol 189, 433-443 https://doi.org/10.4049/jimmunol.1101375
  77. Jacobs JL and Coyne CB (2013) Mechanisms of MAVS Regulation at the Mitochondrial Membrane. J Mol Biol 425, 5009-5019 https://doi.org/10.1016/j.jmb.2013.10.007
  78. Seth RB, Sun LJ, Ea CK and Chen ZJJ (2005) Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappa B and IRF3. Cell 122, 669-682 https://doi.org/10.1016/j.cell.2005.08.012
  79. Subramanian N, Natarajan K, Clatworthy MR, Wang Z and Germain RN (2013) The Adaptor MAVS Promotes NLRP3 Mitochondrial Localization and Inflammasome Activation. Cell 153, 348-361 https://doi.org/10.1016/j.cell.2013.02.054
  80. Castanier C, Garcin D, Vazquez A and Arnoult D (2010) Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway. EMBO Rep 11, 133-138 https://doi.org/10.1038/embor.2009.258
  81. Yasukawa K, Oshiumi H, Takeda M et al (2009) Mitofusin 2 Inhibits Mitochondrial Antiviral Signaling. Sci Signal 2, ra47 https://doi.org/10.1126/scisignal.2000287
  82. Tang ED and Wang CY (2009) MAVS Self-Association Mediates Antiviral Innate Immune Signaling. J Virol 83, 3420-3428 https://doi.org/10.1128/JVI.02623-08
  83. Vogel RO, Janssen RJRJ, van den Brand MAM et al (2007) Cytosolic signaling protein Ecsit also localizes to mitochondria where it interacts with chaperone NDUFAF1 and functions in complex I assembly. Gene Dev 21, 615-624 https://doi.org/10.1101/gad.408407
  84. Geng J, Sun XF, Wang P et al (2015) Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity. Nat Immunol 16, 1142-1152 https://doi.org/10.1038/ni.3268
  85. Carneiro FRG, Lepelley A, Seeley JJ, Hayden MS and Ghosh S (2018) An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages. Cell Rep 22, 2654-2666 https://doi.org/10.1016/j.celrep.2018.02.051
  86. Shi HX, Liu X, Wang Q et al (2011) Mitochondrial Ubiquitin Ligase MARCH5 Promotes TLR7 Signaling by Attenuating TANK Action. PLoS Pathog 7, e1002057 https://doi.org/10.1371/journal.ppat.1002057
  87. Wilkins HM, Carl SM, Greenlief ACS, Festoff BW and Swerdlow RH (2014) Bioenergetic Dysfunction and Inflammation in Alzheimer's Disease: A Possible Connection. Front Aging Neurosci 6, 311
  88. Wilkins HM, Weidling IW, Ji Y and Swerdlow RH (2017) Mitochondria-Derived Damage-Associated Molecular Patterns in Neurodegeneration. Front Immunol 8, 508 https://doi.org/10.3389/fimmu.2017.00508
  89. Bajwa E, Pointer CB and Klegeris A (2019) The Role of Mitochondrial Damage-Associated Molecular Patterns in Chronic Neuroinflammation. Mediators Inflammation 2019, 4050796 https://doi.org/10.1155/2019/4050796
  90. Wilkins HM, Koppel SJ, Weidling IW et al (2016) Extracellular Mitochondria and Mitochondrial Components Act as Damage-Associated Molecular Pattern Molecules in the Mouse Brain. J Neuroimmune Pharmacol 11, 622-628 https://doi.org/10.1007/s11481-016-9704-7
  91. Guerreiro R, Wojtas A, Bras J et al (2013) TREM2 variants in Alzheimer's disease. N Engl J Med 368, 117-127 https://doi.org/10.1056/NEJMoa1211851
  92. Korvatska O, Leverenz JB, Jayadev S et al (2015) R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study. JAMA Neurol 72, 920-927 https://doi.org/10.1001/jamaneurol.2015.0979
  93. Wang Y, Cella M, Mallinson K et al (2015) TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160, 1061-1071 https://doi.org/10.1016/j.cell.2015.01.049
  94. Turnbull IR, Gilfillan S, Cella M et al (2006) Cutting edge: TREM-2 attenuates macrophage activation. J Immunol 177, 3520-3524 https://doi.org/10.4049/jimmunol.177.6.3520
  95. Jiang T, Zhang YD, Chen Q et al (2016) TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice. Neuropharmacology 105, 196-206 https://doi.org/10.1016/j.neuropharm.2016.01.028
  96. Podlesniy P, Figueiro-Silva J, Llado A et al (2013) Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease. Ann Neurol 74, 655-668 https://doi.org/10.1002/ana.23955
  97. Thubron EB, Rosa HS, Hodges A et al (2019) Regional mitochondrial DNA and cell-type changes in post-mortem brains of non-diabetic Alzheimer's disease are not present in diabetic Alzheimer's disease. Sci Rep 9, 11386 https://doi.org/10.1038/s41598-019-47783-4
  98. Ruggiero FM, Cafagna F, Petruzzella V, Gadaleta MN and Quagliariello E (1992) Lipid composition in synaptic and nonsynaptic mitochondria from rat brains and effect of aging. J Neurochem 59, 487-491 https://doi.org/10.1111/j.1471-4159.1992.tb09396.x
  99. Pointer CB and Klegeris A (2017) Cardiolipin in Central Nervous System Physiology and Pathology. Cell Mol Neurobiol 37, 1161-1172 https://doi.org/10.1007/s10571-016-0458-9
  100. Petrosillo G, Matera M, Casanova G, Ruggiero FM and Paradies G (2008) Mitochondrial dysfunction in rat brain with aging Involvement of complex I, reactive oxygen species and cardiolipin. Neurochem Int 53, 126-131 https://doi.org/10.1016/j.neuint.2008.07.001
  101. Perier C, Tieu K, Guegan C et al (2005) Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage. Proc Natl Acad Sci U S A 102, 19126-19131 https://doi.org/10.1073/pnas.0508215102
  102. Little JP, Simtchouk S, Schindler SM et al (2014) Mitochondrial transcription factor A (Tfam) is a proinflammatory extracellular signaling molecule recognized by brain microglia. Mol Cell Neurosci 60, 88-96 https://doi.org/10.1016/j.mcn.2014.04.003
  103. Schindler SM, Frank MG, Annis JL, Maier SF and Klegeris A (2018) Pattern recognition receptors mediate pro-inflammatory effects of extracellular mitochondrial transcription factor A (TFAM). Mol Cell Neurosci 89, 71-79 https://doi.org/10.1016/j.mcn.2018.04.005
  104. Julian MW, Shao G, Vangundy ZC, Papenfuss TL and Crouser ED (2013) Mitochondrial transcription factor A, an endogenous danger signal, promotes $TNF{\alpha}$ release via RAGE- and TLR9-responsive plasmacytoid dendritic cells. PLoS One 8, e72354-e72354
  105. Verdier Y, Zarandi M and Penke B (2004) Amyloid beta-peptide interactions with neuronal and glial cell plasma membrane: binding sites and implications for Alzheimer's disease. J Pept Sci 10, 229-248 https://doi.org/10.1002/psc.573
  106. Xie J, Mendez JD, Mendez-Valenzuela V and Aguilar-Hernandez MM (2013) Cellular signalling of the receptor for advanced glycation end products (RAGE). Cell Signal 25, 2185-2197 https://doi.org/10.1016/j.cellsig.2013.06.013
  107. Lue LF, Walker DG, Brachova L et al (2001) Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer's disease: identification of a cellular activation mechanism. Exp Neurol 171, 29-45 https://doi.org/10.1006/exnr.2001.7732
  108. Papaliagkas V, Anogeianakis G, Tsolaki M, Koliakos G and Kimiskidis V (2009) Prediction of Conversion from Mild Cognitive Impairment to Alzheimer's Disease by CSF Cytochrome c Levels and N200 Latency. Curr Alzheimer Res 6, 279-284 https://doi.org/10.2174/156720509788486626
  109. Takuma K, Yan SS, Stern DM and Yamada K (2005) Mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis in Alzheimer's disease. J Pharmacol Sci 97, 312-316 https://doi.org/10.1254/jphs.CPJ04006X
  110. Krysko DV, Agostinis P, Krysko O et al (2011) Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation. Trends Immunol 32, 157-164 https://doi.org/10.1016/j.it.2011.01.005
  111. Gouveia A, Bajwa E and Klegeris A (2017) Extracellular cytochrome c as an intercellular signaling molecule regulating microglial functions. Biochim Biophys Acta Gen Subj 1861, 2274-2281 https://doi.org/10.1016/j.bbagen.2017.06.017
  112. Oyewole AO and Birch-Machin MA (2015) Mitochondriatargeted antioxidants. FASEB J 29, 4766-4771 https://doi.org/10.1096/fj.15-275404
  113. Jauslin ML, Meier T, Smith RA and Murphy MP (2003) Mitochondria-targeted antioxidants protect Friedreich Ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants. FASEB J 17, 1972-1974
  114. Gioscia-Ryan RA, LaRocca TJ, Sindler AL, Zigler MC, Murphy MP and Seals DR (2014) Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice. J Physiol 592, 2549-2561 https://doi.org/10.1113/jphysiol.2013.268680
  115. Jin H, Kanthasamy A, Ghosh A, Anantharam V, Kalyanaraman B and Kanthasamy AG (2014) Mitochondriatargeted antioxidants for treatment of Parkinson's disease: preclinical and clinical outcomes. Biochimica et biophysica acta 1842, 1282-1294 https://doi.org/10.1016/j.bbadis.2013.09.007
  116. Dashdorj A, Jyothi KR, Lim S et al (2013) Mitochondriatargeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasomemediated inflammatory cytokines. BMC Med 11, 178 https://doi.org/10.1186/1741-7015-11-178
  117. Asano T, Koike M, Sakata S et al (2015) Possible involvement of iron-induced oxidative insults in neurodegeneration. Neurosci Lett 588, 29-35 https://doi.org/10.1016/j.neulet.2014.12.052
  118. Mena NP, Urrutia PJ, Lourido F, Carrasco CM and Nunez MT (2015) Mitochondrial iron homeostasis and its dysfunctions in neurodegenerative disorders. Mitochondrion 21, 92-105 https://doi.org/10.1016/j.mito.2015.02.001
  119. Thomsen MS, Andersen MV, Christoffersen PR, Jensen MD, Lichota J and Moos T (2015) Neurodegeneration with inflammation is accompanied by accumulation of iron and ferritin in microglia and neurons. Neurobiol Dis 81, 108-118 https://doi.org/10.1016/j.nbd.2015.03.013
  120. Smigrodzki RM and Khan SM (2005) Mitochondrial microheteroplasmy and a theory of aging and age-related disease. Rejuvenation Res 8, 172-198 https://doi.org/10.1089/rej.2005.8.172
  121. Casoli T, Spazzafumo L, Di Stefano G and Conti F (2015) Role of diffuse low-level heteroplasmy of mitochondrial DNA in Alzheimer's disease neurodegeneration. Front Aging Neurosci 7, 142-142
  122. Onyango IG (2018) Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer's disease. Neural Regen Res 13, 19-25 https://doi.org/10.4103/1673-5374.224362
  123. Jo A, Ham S, Lee GH et al (2015) Efficient Mitochondrial Genome Editing by CRISPR/Cas9. Biomed Res Int 2015, 305716 https://doi.org/10.1155/2015/305716
  124. Hashimoto M, Bacman SR, Peralta S et al (2015) MitoTALEN: A General Approach to Reduce Mutant mtDNA Loads and Restore Oxidative Phosphorylation Function in Mitochondrial Diseases. Mol Ther 23, 1592-1599 https://doi.org/10.1038/mt.2015.126
  125. Zhong Y, Hu YJ, Chen B et al (2011) Mitochondrial transcription factor A overexpression and base excision repair deficiency in the inner ear of rats with D-galactose-induced aging. FEBS J 278, 2500-2510 https://doi.org/10.1111/j.1742-4658.2011.08176.x
  126. Hayashi Y, Yoshida M, Yamato M et al (2008) Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor a in mice. J Neurosci 28, 8624-8634 https://doi.org/10.1523/JNEUROSCI.1957-08.2008
  127. Xu S, Zhong M, Zhang L et al (2009) Overexpression of Tfam protects mitochondria against beta-amyloidinduced oxidative damage in SH-SY5Y cells. FEBS J 276, 3800-3809 https://doi.org/10.1111/j.1742-4658.2009.07094.x
  128. Oka S, Leon J, Sakumi K et al (2016) Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer's disease. Sci Rep 6, 37889 https://doi.org/10.1038/srep37889
  129. Heneka MT, Kummer MP, Stutz A et al (2013) NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493, 674-678 https://doi.org/10.1038/nature11729
  130. Daniels MJ, Rivers-Auty J, Schilling T et al (2016) Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models. Nat Commun 7, 12504 https://doi.org/10.1038/ncomms12504
  131. Dempsey C, Rubio Araiz A, Bryson KJ et al (2017) Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-beta and cognitive function in APP/PS1 mice. Brain Behav Immun 61, 306-316 https://doi.org/10.1016/j.bbi.2016.12.014
  132. Yin J, Zhao F, Chojnacki JE et al (2018) NLRP3 Inflammasome Inhibitor Ameliorates Amyloid Pathology in a Mouse Model of Alzheimer's Disease. Mol Neurobiol 55, 1977-1987 https://doi.org/10.1007/s12035-017-0467-9
  133. Yang Y, Wang H, Kouadir M, Song H and Shi F (2019) Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death Dis 10, 128 https://doi.org/10.1038/s41419-019-1413-8
  134. Lautrup S, Lou G, Aman Y, Nilsen H, Tao J and Fang EF (2019) Microglial mitophagy mitigates neuroinflammation in Alzheimer's disease. Neurochem Int 129, 104469 https://doi.org/10.1016/j.neuint.2019.104469
  135. 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
  136. Lei Q, Tan J, Yi S, Wu N, Wang Y and Wu H (2018) Mitochonic acid 5 activates the MAPK-ERK-yap signaling pathways to protect mouse microglial BV-2 cells against TNFalpha-induced apoptosis via increased Bnip3-related mitophagy. Cell Mol Biol Lett 23, 14 https://doi.org/10.1186/s11658-018-0081-5
  137. Zhou R, Yazdi AS, Menu P and Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221-225 https://doi.org/10.1038/nature09663
  138. Jiang S, Nandy P, Wang W et al (2018) Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex. Mol Neurodegener 13, 5 https://doi.org/10.1186/s13024-018-0238-8
  139. Park J, Choi H, Min JS et al (2013) Mitochondrial dynamics modulate the expression of pro-inflammatory mediators in microglial cells. J Neurochem 127, 221-232 https://doi.org/10.1111/jnc.12361
  140. Kim H, Lee JY, Park KJ, Kim W-H and Roh GS (2016) A mitochondrial division inhibitor, Mdivi-1, inhibits mitochondrial fragmentation and attenuates kainic acid-induced hippocampal cell death. BMC Neurosci 17, 33 https://doi.org/10.1186/s12868-016-0270-y
  141. Joshi AU, Minhas PS, Liddelow SA et al (2019) Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration. Nat Neurosci 22, 1635-1648 https://doi.org/10.1038/s41593-019-0486-0
  142. Akhter F, Chen D, Yan SF and Yan SS (2017) Mitochondrial Perturbation in Alzheimer's Disease and Diabetes. Prog Mol Biol Transl Sci 146, 341-361 https://doi.org/10.1016/bs.pmbts.2016.12.019
  143. Barber GN (2014) STING-dependent cytosolic DNA sensing pathways. Trends Immunol 35, 88-93 https://doi.org/10.1016/j.it.2013.10.010
  144. Liang Q, Seo GJ, Choi YJ et al (2014) Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses. Cell Host Microbe 15, 228-238 https://doi.org/10.1016/j.chom.2014.01.009
  145. Sliter DA, Martinez J, Hao L et al (2018) Parkin and PINK1 mitigate STING-induced inflammation. Nature 561, 258-262 https://doi.org/10.1038/s41586-018-0448-9