Journal of Molecular Medicine

, Volume 97, Issue 2, pp 153–161 | Cite as

Pathological role of apoptosis signal-regulating kinase 1 in human diseases and its potential as a therapeutic target for cognitive disorders

  • So Yeong Cheon
  • Kyoung Joo ChoEmail author


Cognitive disorders are among the leading causes of health and social issues, as well as socioeconomic burden. Cognitive dysfunction associated with diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, diabetes, and stroke can lead to dementia. Despite extensive efforts, strategies for the prevention and treatment of cognitive dysfunction are scarce. Apoptosis signal-regulating kinase 1 (ASK1) participates in diverse biological pathological processes, such as cell death, survival, and differentiation, and it has been suggested as a therapeutic target in various diseases. However, the role of ASK1 in cognitive dysfunction has not been clearly examined yet. In addition, only a few studies have reported a possible relationship between ASK1 signaling and cognitive deficits. In this review, we summarized experimental evidences regarding the association between ASK1 and the pathogenesis of various diseases. Furthermore, we reviewed preclinical studies supporting the possibility that ASK1 regulation is a promising target for the prevention/treatment of cognitive disorders. Nevertheless, future studies are necessary to investigate the role of ASK1 in the pathogenic mechanisms underlying cognitive dysfunctions, for the translation of preclinical information into clinical application.


Cognitive dysfunction Apoptosis signal-regulating kinase 1 Stroke Dementia Alzheimer’s disease Huntington’s disease Parkinson’s disease Diabetes 


Funding information

This study was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2018R1D1A1B07048587).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Ngandu T, Lehtisalo J, Solomon A, Levalahti E, Ahtiluoto S, Antikainen R, Backman L, Hanninen T, Jula A, Laatikainen T, Lindstrom J, Mangialasche F, Paajanen T, Pajala S, Peltonen M, Rauramaa R, Stigsdotter-Neely A, Strandberg T, Tuomilehto J, Soininen H, Kivipelto M (2015) A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet 385:2255–2263CrossRefGoogle Scholar
  2. 2.
    Klimova B, Valis M, Kuca K (2017) Cognitive decline in normal aging and its prevention: a review on non-pharmacological lifestyle strategies. Clin Interv Aging 12:903–910CrossRefGoogle Scholar
  3. 3.
    Poddar J, Pradhan M, Ganguly G, Chakrabarti S (2018) Biochemical deficits and cognitive decline in brain aging: intervention by dietary supplements. J Chem NeuroanatGoogle Scholar
  4. 4.
    Kennedy G, Hardman RJ, Macpherson H, Scholey AB, Pipingas A (2017) How does exercise reduce the rate of age-associated cognitive decline? A Review of Potential Mechanisms. J Alzheimers Dis 55:1–18CrossRefGoogle Scholar
  5. 5.
    van de Rest O, Berendsen AA, Haveman-Nies A, de Groot LC (2015) Dietary patterns, cognitive decline, and dementia: a systematic review. Adv Nutr 6:154–168CrossRefGoogle Scholar
  6. 6.
    Yano Y, Bakris GL, Inokuchi T, Ohba Y, Tamaki N, Nagata M, Kuwabara M, Yokota N, Eto T, Kuroki M, Shimada K, Kario K (2014) Association of cognitive dysfunction with cardiovascular disease events in elderly hypertensive patients. J Hypertens 32:423–431CrossRefGoogle Scholar
  7. 7.
    Davis MY, Keene CD, Jayadev S, Bird T (2014) The co-occurrence of Alzheimer’s disease and Huntington’s disease: a neuropathological study of 15 elderly Huntington’s disease subjects. J Huntingtons Dis 3:209–217Google Scholar
  8. 8.
    Svenningsson P, Westman E, Ballard C, Aarsland D (2012) Cognitive impairment in patients with Parkinson’s disease: diagnosis, biomarkers, and treatment. Lancet Neurol 11:697–707CrossRefGoogle Scholar
  9. 9.
    Aarsland D, Creese B, Politis M, Chaudhuri KR, Ffytche DH, Weintraub D, Ballard C (2017) Cognitive decline in Parkinson disease. Nat Rev Neurol 13:217–231CrossRefGoogle Scholar
  10. 10.
    Koekkoek PS, Kappelle LJ, van den Berg E, Rutten GE, Biessels GJ (2015) Cognitive function in patients with diabetes mellitus: guidance for daily care. Lancet Neurol 14:329–340CrossRefGoogle Scholar
  11. 11.
    Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y (1997) Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275:90–94CrossRefGoogle Scholar
  12. 12.
    Cheon SY, Kim EJ, Kim JM, Koo BN (2018) Cell type-specific mechanisms in the pathogenesis of ischemic stroke: the role of apoptosis signal-regulating kinase 1. Oxidative Med Cell Longev 2018:2596043CrossRefGoogle Scholar
  13. 13.
    Cho KJ, Cheon SY, Kim GW (2016) Apoptosis signal-regulating kinase 1 mediates striatal degeneration via the regulation of C1q. Sci Rep 6:18840CrossRefGoogle Scholar
  14. 14.
    Song J, Cho KJ, Cheon SY, Kim SH, Park KA, Lee WT, Lee JE (2013) Apoptosis signal-regulating kinase 1 (ASK1) is linked to neural stem cell differentiation after ischemic brain injury. Exp Mol Med 45:e69CrossRefGoogle Scholar
  15. 15.
    Takeda K, Hatai T, Hamazaki TS, Nishitoh H, Saitoh M, Ichijo H (2000) Apoptosis signal-regulating kinase 1 (ASK1) induces neuronal differentiation and survival of PC12 cells. J Biol Chem 275:9805–9813CrossRefGoogle Scholar
  16. 16.
    Toyama K, Koibuchi N, Hasegawa Y, Uekawa K, Yasuda O, Sueta D, Nakagawa T, Ma M, Kusaka H, Lin B, Ogawa H, Ichijo H, Kim-Mitsuyama S (2015) ASK1 is involved in cognitive impairment caused by long-term high-fat diet feeding in mice. Sci Rep 5:10844CrossRefGoogle Scholar
  17. 17.
    Kadowaki H, Nishitoh H, Urano F, Sadamitsu C, Matsuzawa A, Takeda K, Masutani H, Yodoi J, Urano Y, Nagano T, Ichijo H (2005) Amyloid beta induces neuronal cell death through ROS-mediated ASK1 activation. Cell Death Differ 12:19–24CrossRefGoogle Scholar
  18. 18.
    Song J, Cheon SY, Lee WT, Park KA, Lee JE (2015) The effect of ASK1 on vascular permeability and edema formation in cerebral ischemia. Brain Res 1595:143–155CrossRefGoogle Scholar
  19. 19.
    Izumiya Y, Kim S, Izumi Y, Yoshida K, Yoshiyama M, Matsuzawa A, Ichijo H, Iwao H (2003) Apoptosis signal-regulating kinase 1 plays a pivotal role in angiotensin II-induced cardiac hypertrophy and remodeling. Circ Res 93:874–883CrossRefGoogle Scholar
  20. 20.
    Budas GR, Boehm M, Kojonazarov B, Viswanathan G, Tian X, Veeroju S, Novoyatleva T, Grimminger F, Hinojosa-Kirschenbaum F, Ghofrani HA, Weissmann N, Seeger W, Liles JT, Schermuly RT (2018) ASK1 inhibition halts disease progression in preclinical models of pulmonary arterial hypertension. Am J Respir Crit Care Med 197:373–385CrossRefGoogle Scholar
  21. 21.
    Wen X, Qi D, Sun Y, Huang X, Zhang F, Wu J, Fu Y, Ma K, Du Y, Dong H, Liu Y, Liu H, Song Y (2014) H(2) S attenuates cognitive deficits through Akt1/JNK3 signaling pathway in ischemic stroke. Behav Brain Res 269:6–14CrossRefGoogle Scholar
  22. 22.
    Toyama K, Koibuchi N, Uekawa K, Hasegawa Y, Kataoka K, Katayama T, Sueta D, Ma MJ, Nakagawa T, Yasuda O, Tomimoto H, Ichijo H, Ogawa H, Kim-Mitsuyama S (2014) Apoptosis signal-regulating kinase 1 is a novel target molecule for cognitive impairment induced by chronic cerebral hypoperfusion. Arterioscler Thromb Vasc Biol 34:616–625CrossRefGoogle Scholar
  23. 23.
    Pei B, Yang M, Qi X, Shen X, Chen X, Zhang F (2016) Quercetin ameliorates ischemia/reperfusion-induced cognitive deficits by inhibiting ASK1/JNK3/caspase-3 by enhancing the Akt signaling pathway. Biochem Biophys Res Commun 478:199–205CrossRefGoogle Scholar
  24. 24.
    Hunter S, Brayne C (2018) Understanding the roles of mutations in the amyloid precursor protein in Alzheimer disease. Mol Psychiatry 23:81–93CrossRefGoogle Scholar
  25. 25.
    Turner PR, O’Connor K, Tate WP, Abraham WC (2003) Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol 70:1–32CrossRefGoogle Scholar
  26. 26.
    Sclip A, Antoniou X, Colombo A, Camici GG, Pozzi L, Cardinetti D, Feligioni M, Veglianese P, Bahlmann FH, Cervo L, Balducci C, Costa C, Tozzi A, Calabresi P, Forloni G, Borsello T (2011) c-Jun N-terminal kinase regulates soluble Abeta oligomers and cognitive impairment in AD mouse model. J Biol Chem 286:43871–43880CrossRefGoogle Scholar
  27. 27.
    Hasegawa Y, Toyama K, Uekawa K, Ichijo H, Kim-Mitsuyama S (2018) Role of ASK1/p38 Cascade in a mouse model of Alzheimer’s disease and brain aging. J Alzheimers Dis 61:259–263CrossRefGoogle Scholar
  28. 28.
    Liu J, Li C, Xing G, Zhou L, Dong M, Geng Y, Li X, Li J, Wang G, Zou D, Niu Y (2010) Beta-asarone attenuates neuronal apoptosis induced by Beta amyloid in rat hippocampus. Yakugaku Zasshi 130:737–746CrossRefGoogle Scholar
  29. 29.
    Akterin S, Cowburn RF, Miranda-Vizuete A, Jimenez A, Bogdanovic N, Winblad B, Cedazo-Minguez A (2006) Involvement of glutaredoxin-1 and thioredoxin-1 in beta-amyloid toxicity and Alzheimer’s disease. Cell Death Differ 13:1454–1465CrossRefGoogle Scholar
  30. 30.
    Hsu MJ, Hsu CY, Chen BC, Chen MC, Ou G, Lin CH (2007) Apoptosis signal-regulating kinase 1 in amyloid beta peptide-induced cerebral endothelial cell apoptosis. J Neurosci 27:5719–5729CrossRefGoogle Scholar
  31. 31.
    Galvan V, Banwait S, Spilman P, Gorostiza OF, Peel A, Ataie M, Crippen D, Huang W, Sidhu G, Ichijo H, Bredesen DE (2007) Interaction of ASK1 and the beta-amyloid precursor protein in a stress-signaling complex. Neurobiol Dis 28:65–75CrossRefGoogle Scholar
  32. 32.
    Morishima Y, Gotoh Y, Zieg J, Barrett T, Takano H, Flavell R, Davis RJ, Shirasaki Y, Greenberg ME (2001) Beta-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand. J Neurosci 21:7551–7560CrossRefGoogle Scholar
  33. 33.
    Yoon JH, Mo JS, Kim MY, Ann EJ, Ahn JS, Jo EH, Lee HJ, Lee YC, Seol W, Yarmoluk SM, Gasser T, Kahle PJ, Liu GH, Belmonte JCI, Park HS (2017) LRRK2 functions as a scaffolding kinase of ASK1-mediated neuronal cell death. Biochim Biophys Acta 1864:2356–2368CrossRefGoogle Scholar
  34. 34.
    Lee KW, Woo JM, Im JY, Park ES, He L, Ichijo H, Junn E, Mouradian MM (2015) Apoptosis signal-regulating kinase 1 modulates the phenotype of alpha-synuclein transgenic mice. Neurobiol Aging 36:519–526CrossRefGoogle Scholar
  35. 35.
    Pan J, Li H, Zhang B, Xiong R, Zhang Y, Kang WY, Chen W, Zhao ZB, Chen SD (2015) Small peptide inhibitor of JNK3 protects dopaminergic neurons from MPTP induced injury via inhibiting the ASK1-JNK3 signaling pathway. PLoS One 10:e0119204CrossRefGoogle Scholar
  36. 36.
    Lee KW, Zhao X, Im JY, Grosso H, Jang WH, Chan TW, Sonsalla PK, German DC, Ichijo H, Junn E, Mouradian MM (2012) Apoptosis signal-regulating kinase 1 mediates MPTP toxicity and regulates glial activation. PLoS One 7:e29935CrossRefGoogle Scholar
  37. 37.
    Junn E, Taniguchi H, Jeong BS, Zhao X, Ichijo H, Mouradian MM (2005) Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death. Proc Natl Acad Sci U S A 102:9691–9696CrossRefGoogle Scholar
  38. 38.
    Hu X, Weng Z, Chu CT, Zhang L, Cao G, Gao Y, Signore A, Zhu J, Hastings T, Greenamyre JT, Chen J (2011) Peroxiredoxin-2 protects against 6-hydroxydopamine-induced dopaminergic neurodegeneration via attenuation of the apoptosis signal-regulating kinase (ASK1) signaling cascade. J Neurosci 31:247–261CrossRefGoogle Scholar
  39. 39.
    Ouyang M, Shen X (2006) Critical role of ASK1 in the 6-hydroxydopamine-induced apoptosis in human neuroblastoma SH-SY5Y cells. J Neurochem 97:234–244CrossRefGoogle Scholar
  40. 40.
    Karunakaran S, Diwakar L, Saeed U, Agarwal V, Ramakrishnan S, Iyengar S, Ravindranath V (2007) Activation of apoptosis signal regulating kinase 1 (ASK1) and translocation of death-associated protein, Daxx, in substantia nigra pars compacta in a mouse model of Parkinson’s disease: protection by alpha-lipoic acid. FASEB J 21:2226–2236CrossRefGoogle Scholar
  41. 41.
    Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, Nance M, Ross CA, Scahill RI, Wetzel R, Wild EJ, Tabrizi SJ (2015) Huntington disease. Nat Rev Dis Primers 1:15005CrossRefGoogle Scholar
  42. 42.
    McColgan P, Tabrizi SJ (2018) Huntington’s disease: a clinical review. Eur J Neurol 25:24–34CrossRefGoogle Scholar
  43. 43.
    Minn Y, Cho KJ, Kim HW, Kim HJ, Suk SH, Lee BI, Kim GW (2008) Induction of apoptosis signal-regulating kinase 1 and oxidative stress mediate age-dependent vulnerability to 3-nitropropionic acid in the mouse striatum. Neurosci Lett 430:142–146CrossRefGoogle Scholar
  44. 44.
    Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, Hori S, Kakizuka A, Ichijo H (2002) ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev 16:1345–1355CrossRefGoogle Scholar
  45. 45.
    Arning L, Monte D, Hansen W, Wieczorek S, Jagiello P, Akkad DA, Andrich J, Kraus PH, Saft C, Epplen JT (2008) ASK1 and MAP 2K6 as modifiers of age at onset in Huntington’s disease. J Mol Med (Berl) 86:485–490CrossRefGoogle Scholar
  46. 46.
    Cayzac S, Delcasso S, Paz V, Jeantet Y, Cho YH (2011) Changes in striatal procedural memory coding correlate with learning deficits in a mouse model of Huntington disease. Proc Natl Acad Sci U S A 108:9280–9285CrossRefGoogle Scholar
  47. 47.
    Aylward EH, Sparks BF, Field KM, Yallapragada V, Shpritz BD, Rosenblatt A, Brandt J, Gourley LM, Liang K, Zhou H, Margolis RL, Ross CA (2004) Onset and rate of striatal atrophy in preclinical Huntington disease. Neurology 63:66–72CrossRefGoogle Scholar
  48. 48.
    Lange KW, Sahakian BJ, Quinn NP, Marsden CD, Robbins TW (1995) Comparison of executive and visuospatial memory function in Huntington’s disease and dementia of Alzheimer type matched for degree of dementia. J Neurol Neurosurg Psychiatry 58:598–606CrossRefGoogle Scholar
  49. 49.
    Lione LA, Carter RJ, Hunt MJ, Bates GP, Morton AJ, Dunnett SB (1999) Selective discrimination learning impairments in mice expressing the human Huntington’s disease mutation. J Neurosci 19:10428–10437CrossRefGoogle Scholar
  50. 50.
    Lin L, Cao J, Yang SS, Fu ZQ, Zeng P, Chu J, Ning LN, Zhang T, Shi Y, Tian Q, Zhou XW, Wang JZ (2018) Endoplasmic reticulum stress induces spatial memory deficits by activating GSK-3. J Cell Mol Med 22:3489–3502CrossRefGoogle Scholar
  51. 51.
    Shen FY, Song YC, Guo F, Xu ZD, Li Q, Zhang B, Ma YQ, Zhang YQ, Lin R, Li Y, Liu ZQ (2018) Cognitive impairment and endoplasmic reticulum stress induced by repeated short-term sevoflurane exposure in early life of rats. Front Psychiatry 9:332CrossRefGoogle Scholar
  52. 52.
    Cho KJ, Kim HW, Cheon SY, Lee JE, Kim GW (2013) Apoptosis signal-regulating kinase-1 aggravates ROS-mediated striatal degeneration in 3-nitropropionic acid-infused mice. Biochem Biophys Res Commun 441:280–285CrossRefGoogle Scholar
  53. 53.
    Cho KJ, Kim GW (2015) Differential caspase activity in the cortex and striatum with chronic infusion of 3-nitropropionic acid. Biochem Biophys Res Commun 465:631–637CrossRefGoogle Scholar
  54. 54.
    Cho KJ, Lee BI, Cheon SY, Kim HW, Kim HJ, Kim GW (2009) Inhibition of apoptosis signal-regulating kinase 1 reduces endoplasmic reticulum stress and nuclear huntingtin fragments in a mouse model of Huntington disease. Neuroscience 163:1128–1134CrossRefGoogle Scholar
  55. 55.
    Desrocher M, Rovet J (2004) Neurocognitive correlates of type 1 diabetes mellitus in childhood. Child Neuropsychol 10:36–52CrossRefGoogle Scholar
  56. 56.
    Biessels GJ, Deary IJ, Ryan CM (2008) Cognition and diabetes: a lifespan perspective. Lancet Neurol 7:184–190CrossRefGoogle Scholar
  57. 57.
    Musen G, Lyoo IK, Sparks CR, Weinger K, Hwang J, Ryan CM, Jimerson DC, Hennen J, Renshaw PF, Jacobson AM (2006) Effects of type 1 diabetes on gray matter density as measured by voxel-based morphometry. Diabetes 55:326–333CrossRefGoogle Scholar
  58. 58.
    Wessels AM, Rombouts SA, Remijnse PL, Boom Y, Scheltens P, Barkhof F, Heine RJ, Snoek FJ (2007) Cognitive performance in type 1 diabetes patients is associated with cerebral white matter volume. Diabetologia 50:1763–1769CrossRefGoogle Scholar
  59. 59.
    Moheet A, Mangia S, Seaquist ER (2015) Impact of diabetes on cognitive function and brain structure. Ann N Y Acad Sci 1353:60–71CrossRefGoogle Scholar
  60. 60.
    Zhou H, Lu W, Shi Y, Bai F, Chang J, Yuan Y, Teng G, Zhang Z (2010) Impairments in cognition and resting-state connectivity of the hippocampus in elderly subjects with type 2 diabetes. Neurosci Lett 473:5–10CrossRefGoogle Scholar
  61. 61.
    Yamaguchi K, Takeda K, Kadowaki H, Ueda I, Namba Y, Ouchi Y, Nishitoh H, Ichijo H (2013) Involvement of ASK1-p38 pathway in the pathogenesis of diabetes triggered by pancreatic ss cell exhaustion. Biochim Biophys Acta 1830:3656–3663CrossRefGoogle Scholar
  62. 62.
    Pepin E, Higa A, Schuster-Klein C, Bernard C, Sulpice T, Guardiola B, Chevet E, Alquier T (2014) Deletion of apoptosis signal-regulating kinase 1 (ASK1) protects pancreatic beta-cells from stress-induced death but not from glucose homeostasis alterations under pro-inflammatory conditions. PLoS One 9:e112714CrossRefGoogle Scholar
  63. 63.
    Pedersen M, Pedersen KK, Bruunsgaard H, Krabbe KS, Thomsen C, Faerch K, Pedersen BK, Mortensen EL (2012) Cognitive functions in middle aged individuals are related to metabolic disturbances and aerobic capacity: a cross-sectional study. PLoS One 7:e51132CrossRefGoogle Scholar
  64. 64.
    Park S, Kim DS, Kang S, Moon NR (2013) beta-Amyloid-induced cognitive dysfunction impairs glucose homeostasis by increasing insulin resistance and decreasing beta-cell mass in non-diabetic and diabetic rats. Metabolism 62:1749–1760CrossRefGoogle Scholar
  65. 65.
    Ding J, Strachan MW, Reynolds RM, Frier BM, Deary IJ, Fowkes FG, Lee AJ, McKnight J, Halpin P, Swa K, Price JF, Edinburgh Type 2 Diabetes Study I (2010) Diabetic retinopathy and cognitive decline in older people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes 59:2883–2889CrossRefGoogle Scholar
  66. 66.
    Alosco ML, Spitznagel MB, van Dulmen M, Raz N, Cohen R, Sweet LH, Colbert LH, Josephson R, Hughes J, Rosneck J, et al. (2012) The additive effects of type-2 diabetes on cognitive function in older adults with heart failure. Cardiol Res Pract 2012:348054Google Scholar
  67. 67.
    Thandavarayan RA, Watanabe K, Ma M, Veeraveedu PT, Gurusamy N, Palaniyandi SS, Zhang S, Muslin AJ, Kodama M, Aizawa Y (2008) 14-3-3 protein regulates Ask1 signaling and protects against diabetic cardiomyopathy. Biochem Pharmacol 75:1797–1806CrossRefGoogle Scholar
  68. 68.
    Umegaki H, Iimuro S, Shinozaki T, Araki A, Sakurai T, Iijima K, Ohashi Y, Ito H, Japanese Elderly Diabetes Intervention Trial Study G (2012) Risk factors associated with cognitive decline in the elderly with type 2 diabetes: baseline data analysis of the Japanese Elderly Diabetes Intervention Trial. Geriatr Gerontol Int 12(Suppl 1):103–109CrossRefGoogle Scholar
  69. 69.
    Tesch GH, Ma FY, Han Y, Liles JT, Breckenridge DG, Nikolic-Paterson DJ (2015) ASK1 inhibitor halts progression of diabetic nephropathy in Nos3-deficient mice. Diabetes 64:3903–3913CrossRefGoogle Scholar
  70. 70.
    Terada Y, Inoshita S, Kuwana H, Kobayashi T, Okado T, Ichijo H, Sasaki S (2007) Important role of apoptosis signal-regulating kinase 1 in ischemic acute kidney injury. Biochem Biophys Res Commun 364:1043–1049CrossRefGoogle Scholar
  71. 71.
    Ma FY, Tesch GH, Nikolic-Paterson DJ (2014) ASK1/p38 signaling in renal tubular epithelial cells promotes renal fibrosis in the mouse obstructed kidney. Am J Physiol Renal Physiol 307:F1263–F1273CrossRefGoogle Scholar
  72. 72.
    Ihara M, Kalaria RN (2014) Understanding and preventing the development of post-stroke dementia. Expert Rev Neurother 14:1067–1077CrossRefGoogle Scholar
  73. 73.
    Vijayan M, Kumar S, Bhatti JS, Reddy PH (2017) Molecular links and biomarkers of stroke, vascular dementia, and Alzheimer’s disease. Prog Mol Biol Transl Sci 146:95–126CrossRefGoogle Scholar
  74. 74.
    Sahathevan R, Brodtmann A, Donnan GA (2012) Dementia, stroke, and vascular risk factors; a review. Int J Stroke 7:61–73CrossRefGoogle Scholar
  75. 75.
    Tatemichi TK, Desmond DW, Mayeux R, Paik M, Stern Y, Sano M, Remien RH, Williams JB, Mohr JP, Hauser WA et al (1992) Dementia after stroke: baseline frequency, risks, and clinical features in a hospitalized cohort. Neurology 42:1185–1193CrossRefGoogle Scholar
  76. 76.
    Wiesmann M, Kiliaan AJ, Claassen JA (2013) Vascular aspects of cognitive impairment and dementia. J Cereb Blood Flow Metab 33:1696–1706CrossRefGoogle Scholar
  77. 77.
    Pasi M, Poggesi A, Salvadori E, Pantoni L (2012) Post-stroke dementia and cognitive impairment. Front Neurol Neurosci 30:65–69CrossRefGoogle Scholar
  78. 78.
    O’Brien JT, Thomas A (2015) Vascular dementia. Lancet 386:1698–1706CrossRefGoogle Scholar
  79. 79.
    Garcia JH (1975) The neuropathology of stroke. Hum Pathol 6:583–598CrossRefGoogle Scholar
  80. 80.
    Venkat P, Chopp M, Chen J (2015) Models and mechanisms of vascular dementia. Exp Neurol 272:97–108CrossRefGoogle Scholar
  81. 81.
    Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, Launer LJ, Laurent S, Lopez OL, Nyenhuis D, Petersen RC, Schneider JA, Tzourio C, Arnett DK, Bennett DA, Chui HC, Higashida RT, Lindquist R, Nilsson PM, Roman GC, Sellke FW, Seshadri S, American Heart Association Stroke Council CoE, Prevention CoCNCoCR, Intervention, Council on Cardiovascular S, Anesthesia (2011) Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42:2672–2713CrossRefGoogle Scholar
  82. 82.
    Thal DR, Grinberg LT, Attems J (2012) Vascular dementia: different forms of vessel disorders contribute to the development of dementia in the elderly brain. Exp Gerontol 47:816–824CrossRefGoogle Scholar
  83. 83.
    Kuller LH, Lopez OL, Gottdiener JS, Kitzman DW, Becker JT, Chang Y, Newman AB (2017) Subclinical Atherosclerosis, Cardiac and Kidney Function, Heart Failure, and Dementia in the Very Elderly. J Am Heart Assoc 6Google Scholar
  84. 84.
    Iadecola C (2013) The pathobiology of vascular dementia. Neuron 80:844–866CrossRefGoogle Scholar
  85. 85.
    Kim HW, Cho KJ, Lee SK, Kim GW (2011) Apoptosis signal-regulating kinase 1 (Ask1) targeted small interfering RNA on ischemic neuronal cell death. Brain Res 1412:73–78CrossRefGoogle Scholar
  86. 86.
    Baierle M, Nascimento SN, Moro AM, Brucker N, Freitas F, Gauer B, Durgante J, Bordignon S, Zibetti M, Trentini CM, Duarte MM, Grune T, Breusing N, Garcia SC (2015) Relationship between inflammation and oxidative stress and cognitive decline in the institutionalized elderly. Oxidative Med Cell Longev 2015:804198CrossRefGoogle Scholar
  87. 87.
    Kalaria RN, Akinyemi R, Ihara M (2016) Stroke injury, cognitive impairment and vascular dementia. Biochim Biophys Acta 1862:915–925CrossRefGoogle Scholar
  88. 88.
    Cheon SY, Cho KJ, Song J, Kim GW (2016) Knockdown of apoptosis signal-regulating kinase 1 affects ischaemia-induced astrocyte activation and glial scar formation. Eur J Neurosci 43:912–922CrossRefGoogle Scholar
  89. 89.
    Cheon SY, Kim EJ, Kim JM, Kam EH, Ko BW, Koo BN (2017) Regulation of microglia and macrophage polarization via apoptosis signal-regulating kinase 1 silencing after ischemic/hypoxic injury. Front Mol Neurosci 10:261CrossRefGoogle Scholar
  90. 90.
    Naik MU, Patel P, Derstine R, Turaga R, Chen X, Golla K, Neeves KB, Ichijo H, Naik UP (2017) Ask1 regulates murine platelet granule secretion, thromboxane A2 generation, and thrombus formation. Blood 129:1197–1209CrossRefGoogle Scholar
  91. 91.
    Li H, Liu Y, Lin LT, Wang XR, Du SQ, Yan CQ, He T, Yang JW, Liu CZ (2016) Acupuncture reversed hippocampal mitochondrial dysfunction in vascular dementia rats. Neurochem Int 92:35–42CrossRefGoogle Scholar
  92. 92.
    Wang XR, Shi GX, Yang JW, Yan CQ, Lin LT, Du SQ, Zhu W, He T, Zeng XH, Xu Q, Liu CZ (2015) Acupuncture ameliorates cognitive impairment and hippocampus neuronal loss in experimental vascular dementia through Nrf2-mediated antioxidant response. Free Radic Biol Med 89:1077–1084CrossRefGoogle Scholar
  93. 93.
    Xiao LY, Wang XR, Yang JW, Ye Y, Zhu W, Cao Y, Ma SM, Liu CZ (2018) Acupuncture prevents the impairment of hippocampal LTP through beta1-AR in vascular dementia rats. Mol Neurobiol 55:7677–7690CrossRefGoogle Scholar
  94. 94.
    Zhu W, Wang XR, Du SQ, Yan CQ, Yang NN, Lin LL, Shi GX, Liu CZ (2018) Anti-oxidative and anti-apoptotic effects of acupuncture: role of thioredoxin-1 in the hippocampus of vascular dementia rats. Neuroscience 379:281–291CrossRefGoogle Scholar
  95. 95.
    Ren X, Li C, Liu J, Zhang C, Fu Y, Wang N, Ma H, Lu H, Kong H, Kong L (2017) Thioredoxin plays a key role in retinal neuropathy prior to endothelial damage in diabetic mice. Oncotarget 8:61350–61364Google Scholar
  96. 96.
    Fujisawa T (2017) Therapeutic application of apoptosis signal-regulating kinase 1 inhibitors. Adv Biol Regul 66:85–90CrossRefGoogle Scholar
  97. 97.
    Hao H, Li S, Tang H, Liu B, Cai Y, Shi C, Xiao X (2016) NQDI-1, an inhibitor of ASK1 attenuates acute perinatal hypoxic-ischemic cerebral injury by modulating cell death. Mol Med Rep 13:4585–4592CrossRefGoogle Scholar
  98. 98.
    El Eter E (2013) NQDI 1, an inhibitor of ASK1 attenuates acute ischemic renal injury by modulating oxidative stress and cell death. Cardiovasc Hematol Agents Med Chem 11:179–186CrossRefGoogle Scholar
  99. 99.
    Fujisawa T, Takahashi M, Tsukamoto Y, Yamaguchi N, Nakoji M, Endo M, Kodaira H, Hayashi Y, Nishitoh H, Naguro I, Homma K, Ichijo H (2016) The ASK1-specific inhibitors K811 and K812 prolong survival in a mouse model of amyotrophic lateral sclerosis. Hum Mol Genet 25:245–253CrossRefGoogle Scholar
  100. 100.
    Toldo S, Breckenridge DG, Mezzaroma E, Van Tassell BW, Shryock J, Kannan H, Phan D, Budas G, Farkas D, Lesnefsky E, Voelkel N, Abbate A (2012) Inhibition of apoptosis signal-regulating kinase 1 reduces myocardial ischemia-reperfusion injury in the mouse. J Am Heart Assoc 1:e002360CrossRefGoogle Scholar
  101. 101.
    Umar S, Hedaya O, Singh AK, Ahmed S (2015) Thymoquinone inhibits TNF-alpha-induced inflammation and cell adhesion in rheumatoid arthritis synovial fibroblasts by ASK1 regulation. Toxicol Appl Pharmacol 287:299–305CrossRefGoogle Scholar
  102. 102.
    Luo Y, Gao S, Hao Z, Yang Y, Xie S, Li D, Liu M, Zhou J (2016) Apoptosis signal-regulating kinase 1 exhibits oncogenic activity in pancreatic cancer. Oncotarget 7:75155–75164Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Anesthesia and Pain Research InstituteYonsei University College of MedicineSeoulRepublic of Korea
  2. 2.Department of Life Science, College of Science and EngineeringKyonggi UniversitySuwon-siRepublic of Korea

Personalised recommendations