Skip to main content
SpringerLink
Log in

P25/CDK5-mediated Tau Hyperphosphorylation in Both Ipsilateral and Contralateral Cerebra Contributes to Cognitive Deficits in Post-stroke Mice

  • Original Articles
  • Published:
Current Medical Science Aims and scope Submit manuscript

Abstract

Objective

Post-stroke cognitive impairment (PSCI) develops in approximately one-third of stroke survivors and is associated with ingravescence. Nonetheless, the biochemical mechanisms underlying PSCI remain unclear. The study aimed to establish an ischemic mouse model by means of transient unilateral middle cerebral artery occlusions (MCAOs) and to explore the biochemical mechanisms of p25/cyclin-dependent kinase 5 (CDK5)-mediated tau hyperphosphorylation on the PSCI behavior.

Methods

Cognitive behavior was investigated, followed by the detection of tau hyperphosphorylation, mobilization, activation of kinases and/or inhibition of phosphatases in the lateral and contralateral cerebrum of mice following ischemia in MACO mice. Finally, we treated HEK293/tau cells with oxygen-glucose deprivation (OGD) and a CDK5 inhibitor (Roscovitine) or a GSK3β inhibitor (LiCl) to the roles of CDK5 and GSK3β in mediating ischemia-reperfusion-induced tau phosphorylation.

Results

Ischemia induced cognitive impairments within 2 months, as well as causing tau hyperphosphorylation and its localization to neuronal somata in both ipsilateral and contralateral cerebra. Furthermore, p25 that promotes CDK5 hyperactivation had significantly higher expression in the mice with MCAO than in the shamoperation (control) group, while the expression levels of protein phosphatase 2 (PP2A) and the phosphorylation level at Tyr307 were comparable between the two groups. In addition, the CDK5 inhibitor rescued tau from hyperphosphorylation induced by OGD.

Conclusion

These findings demonstrate that upregulation of CDK5 mediates tau hyperphosphorylation and localization in both ipsilateral and contralateral cerebra, contributing to the pathogenesis of PSCI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Tatemichi TK, Paik M, Bagiella E, et al. Risk of dementia after stroke in a hospitalized cohort: results of a longitudinal study. Neurology, 1994,44(10):1885–1891

    Article  CAS  PubMed  Google Scholar 

  2. Loeb C, Gandolfo C, Croce R, et al. Dementia associated with lacunar infarction. Stroke, 1992,23(9):1225–1229

    Article  CAS  PubMed  Google Scholar 

  3. Allan LM, Rowan EN, Firbank MJ, et al. Long term incidence of dementia, predictors of mortality and pathological diagnosis in older stroke survivors. Brain, 2011,134(Pt 12):3716–3727

    Article  PubMed  Google Scholar 

  4. Tatemichi TK, Desmond DW, Mayeux R, et al. Dementia after stroke: baseline frequency, risks, and clinical features in a hospitalized cohort. Neurology, 1992,42(6):1185–1193

    Article  CAS  PubMed  Google Scholar 

  5. Fride Y, Adamit T, Maeir A, et al. What are the correlates of cognition and participation to return to work after first ever mild stroke?. Top Stroke Rehabil, 2015,22(5):317–325

    Article  CAS  PubMed  Google Scholar 

  6. Mijajlovic MD, Pavlovic A, Brainin M, et al. Post-stroke dementia - a comprehensive review. BMC Med, 2017,15(1):11

    Article  PubMed  PubMed Central  Google Scholar 

  7. Yang C, Hawkins KE, Dore S, et al. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am J Physiol Cell Physiol, 2019,316(2):C135–C153

    Article  CAS  PubMed  Google Scholar 

  8. Doyle KP, Simon RP, Stenzel-Poore MP. Mechanisms of ischemic brain damage. Neuropharmacology, 2008,55(3):310–318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wu M, Zhang M, Yin X, et al. The role of pathological tau in synaptic dysfunction in Alzheimer’s diseases. Transl Neurodegener, 2021,10(1):45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang JZ, Gao X, Wang ZH. The physiology and pathology of microtubule-associated protein tau. Essays Biochem, 2014, 56: 111–123

    Article  PubMed  Google Scholar 

  11. Alonso AC, Zaidi T, Grundke-Iqbal I, et al. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci USA, 1994,91(12):5562–5566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sen T, Saha P, Jiang T, et al. Sulfhydration of AKT triggers Tau-phosphorylation by activating glycogen synthase kinase 3beta in Alzheimer’s disease. Proc Natl Acad Sci USA, 2020,117(8):4418–4427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hoover BR, Reed MN, Su J, et al. Tau Mislocalization to Dendritic Spines Mediates Synaptic Dysfunction Independently of Neurodegeneration. Neuron, 2010,68(6):1067–1081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pao PC, Tsai LH. Three decades of Cdk5. J Biomed Sci, 2021,28(1):79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ao C, Li C, Chen J, et al. The role of Cdk5 in neurological disorders. Front Cell Neurosci, 2022, 16: 951202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Patrick GN, Zukerberg L, Nikolic M, et al. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature, 1999,402(6762):615–622

    Article  CAS  PubMed  Google Scholar 

  17. Lee M S, Kwon Y T, Li M, et al. Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature, 2000,405(6784):360–364

    Article  CAS  PubMed  Google Scholar 

  18. Dhavan R, Tsai LH. A decade of CDK5. Nat Rev Mol Cell Biol, 2001,2(10):749–759

    Article  CAS  PubMed  Google Scholar 

  19. Cheung ZH, Fu AKY, Ip NY. Synaptic roles of Cdk5: Implications in higher cognitive functions and neurodegenerative diseases. Neuron, 2006,50(1):13–18

    Article  CAS  PubMed  Google Scholar 

  20. Arioka M, Tsukamoto M, Ishiguro K, et al. Tau protein kinase II is involved in the regulation of the normal phosphorylation state of tau protein. J Neurochem, 1993,60(2):461–468

    Article  CAS  PubMed  Google Scholar 

  21. Kimura T, Ishiguro K, Hisanaga S. Physiological and pathological phosphorylation of tau by Cdk5. Front Mol Neurosci, 2014, 7: 65

    Article  PubMed  PubMed Central  Google Scholar 

  22. Shukla V, Skuntz S, Pant HC. Deregulated Cdk5 Activity Is Involved in Inducing Alzheimer’s Disease. Arch Med Res, 2012,43(8):655–662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tuo QZ, Lei P, Jackman KA, et al. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry, 2017,22(11):1520–1530

    Article  CAS  PubMed  Google Scholar 

  24. Li DJ, Li YH, Yuan HB, et al. The novel exercise-induced hormone irisin protects against neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotection of physical exercise in cerebral ischemia. Metabolism, 2017, 68: 31–42

    Article  CAS  PubMed  Google Scholar 

  25. Kubota T, Kirino Y. Age-dependent impairment of memory and neurofibrillary tangle formation and clearance in a mouse model of tauopathy. Brain Res, 2021, 1765: 147496

    Article  CAS  PubMed  Google Scholar 

  26. Ramsden M, Kotilinek L, Forster C, et al. Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci, 2005,25(46):10637–10647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Paonessa F, Evans LD, Solanki R, et al. Microtubules Deform the Nuclear Membrane and Disrupt Nucleocytoplasmic Transport in Tau-Mediated Frontotemporal Dementia. Cell Reports, 2019,26(3):582–593

    Article  CAS  PubMed  Google Scholar 

  28. Shin MK, Vazquez-Rosa E, Koh Y, et al. Reducing acetylated tau is neuroprotective in brain injury. Cell, 2021,184(10):2715–2732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang JZ, Grundke-Iqbal I, Iqbal K. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci, 2007,25(1):59–68

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hanger DP, Noble W. Functional implications of glycogen synthase kinase-3-mediated tau phosphorylation. Int J Alzheimers Dis, 2011, 2011: 352805

    PubMed  PubMed Central  Google Scholar 

  31. Gong CX, Shaikh S, Wang JZ, et al. Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J Neurochem, 1995,65(2):732–738

    Article  CAS  PubMed  Google Scholar 

  32. Sandal P, Jong CJ, Merrill RA, et al. Protein phosphatase 2A-structure, function and role in neurodevelopmental disorders. J Cell Sci, 2021,134(13):248187

    Article  Google Scholar 

  33. Seshadri S, Wolf PA. Lifetime risk of stroke and dementia: current concepts, and estimates from the Framingham Study. Lancet Neurol, 2007,6(12):1106–1114

    Article  PubMed  Google Scholar 

  34. Kalmijn S, Launer LJ, Lindemans J, et al. Total homocysteine and cognitive decline in a community-based sample of elderly subjects: the Rotterdam Study. Am J Epidemiol, 1999,150(3):283–289

    Article  CAS  PubMed  Google Scholar 

  35. Rusanen M, Kivipelto M, Quesenberry CP, et al. Heavy smoking in midlife and long-term risk of Alzheimer disease and vascular dementia. Arch Intern Med, 2011,171(4):333–339

    Article  PubMed  Google Scholar 

  36. Tamaoka A, Kalaria RN, Lieberburg I, et al. Identification of a stable fragment of the Alzheimer amyloid precursor containing the beta-protein in brain microvessels. Proc Natl Acad Sci USA, 1992,89(4):1345–1349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fujii H, Takahashi T, Mukai T, et al. Modifications of tau protein after cerebral ischemia and reperfusion in rats are similar to those occurring in Alzheimer’s disease - Hyperphosphorylation and cleavage of 4- and 3-repeat tau. J Cereb Blood Flow Metab, 2017,37(7):2441–2457

    Article  CAS  PubMed  Google Scholar 

  38. Martin L, Latypova X, Wilson CM, et al. Tau protein kinases: involvement in Alzheimer’s disease. Ageing Res Rev, 2013,12(1):289–309

    Article  CAS  PubMed  Google Scholar 

  39. Hanger DP, Anderton BH, Noble W. Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol Med, 2009,15(3):112–119

    Article  CAS  PubMed  Google Scholar 

  40. Liu YQ, Kong C, Gong L, et al. The Association of Post-Stroke Cognitive Impairment and Gut Microbiota and its Corresponding Metabolites. J Alzheimers Dis, 2020,73(4):1455–1466

    Article  PubMed  Google Scholar 

  41. Cai HY, Zhao ZY, Ni LH, et al. Structural and Functional Deficits in Patients with Poststroke Dementia: A Multimodal MRI Study. Neural Plast, 2021:3536234

  42. Hilkens NA, Klijn CJM, Richard E. Blood pressure, blood pressure variability and the risk of poststroke dementia. J Hypertens, 2021,39(9):1859–1864

    Article  CAS  PubMed  Google Scholar 

  43. Pendlebury ST, Rothwell PM. Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol, 2009,8(11):1006–1018

    Article  PubMed  Google Scholar 

  44. Levine DA, Galecki AT, Langa KM, et al. Risk Factors for Poststroke Cognitive Decline: The REGARDS Study (Reasons for Geographic and Racial Differences in Stroke). Stroke, 2018,49(4):987–994

    Article  PubMed  PubMed Central  Google Scholar 

  45. Levine DA, Galecki AT, Langa KM, et al. Trajectory of Cognitive Decline After Incident Stroke. JAMA, 2015,314(1):41–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pollock A, St George B, Fenton M, et al. Top ten research priorities relating to life after stroke. Lancet Neurol, 2012,11(3):209–209

    Article  PubMed  Google Scholar 

  47. Martin L, Latypova X, Wilson CM, et al. Tau protein phosphatases in Alzheimer’s disease: The leading role of PP2A. Ageing Res Rev, 2013,12(1):39–49

    Article  CAS  PubMed  Google Scholar 

  48. El KN, Gratuze M, Papon MA, et al. Insulin dysfunction and Tau pathology. Front Cell Neurosci, 2014, 8: 22

    Google Scholar 

  49. Planel E, Tatebayashi Y, Miyasaka T, et al. Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J Neurosci, 2007,27(50):13635–13648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang Y, Huang NQ, Yan F, et al. Diabetes mellitus and Alzheimer’s disease: GSK-3 beta as a potential link. Behav Brain Res, 2018, 339: 57–65

    Article  CAS  PubMed  Google Scholar 

  51. Liu Y, Liu F, Grundke-Iqbal I, et al. Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes. J Pathol, 2011,225(1):54–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Goncalves RA, Wijesekara N, Fraser PE, et al. The Link Between Tau and Insulin Signaling: Implications for Alzheimer’s Disease and Other Tauopathies. Front Cell Neurosci, 2019, 13: 17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yang LY, Wang HY, Liu LJ, et al. The Role of Insulin/IGF-1/PI3K/Akt/GSK3 beta Signaling in Parkinson’s Disease Dementia. Front Neurosci, 2018, 12: 73

    Article  PubMed  PubMed Central  Google Scholar 

  54. Gabbouj S, Ryhanen S, Marttinen M, et al. Altered Insulin Signaling in Alzheimer’s Disease Brain - Special Emphasis on PI3K-Akt Pathway. Front Neurosci, 2019, 13: 629

    Article  PubMed  PubMed Central  Google Scholar 

  55. Sun KH, de Pablo Y, Vincent F, et al. Novel genetic tools reveal Cdk5’s major role in Golgi fragmentation in Alzheimer’s disease. Mol Biol Cell, 2008,19(7):3052–3069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wei FY, Tomizawa K. Cyclin-dependent kinase 5 (Cdk5): a potential therapeutic target for the treatment of neurodegenerative diseases and diabetes mellitus. Mini Rev Med Chem, 2007,7(10):1070–1074

    Article  CAS  PubMed  Google Scholar 

  57. Meyer DA, Torres-Altoro MI, Tan ZJ, et al. Ischemic Stroke Injury Is Mediated by Aberrant Cdk5. J Neurosci, 2014,34(24):8259–8267

    Article  PubMed  PubMed Central  Google Scholar 

  58. Smith PD, Crocker SJ, Jackson-Lewis V, et al. Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson’s disease. Proc Natl Acad Sci USA, 2003,100(23):13650–13655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gutierrez-Vargas JA, Moreno H, Cardona-Gomez GP. Targeting CDK5 post-stroke provides long-term neuroprotection and rescues synaptic plasticity. J Cereb Blood Flow Metab, 2017,37(6):2208–2223

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, 430056, China

    Jing Yu, Yang Zhao, Xiao-kang Gong, Zheng Liang, Yan-na Zhao, Xin Li, Yu-ju Chen, You-hua Yang, Meng-juan Wu, Xiao-chuan Wang, Xi-ji Shu & Jian Bao

  2. Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, 430056, China

    Jing Yu, Yan-na Zhao, Xin Li, Yu-ju Chen, You-hua Yang, Meng-juan Wu, Xi-ji Shu & Jian Bao

  3. Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Xiao-chuan Wang

Authors
  1. Jing Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao-kang Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zheng Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yan-na Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu-ju Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. You-hua Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Meng-juan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiao-chuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xi-ji Shu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jian Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xi-ji Shu or Jian Bao.

Ethics declarations

The authors declare no conflict of interest.

Additional information

This research was funded by grants from the National Natural Science Foundation of China (No. 31800851), Natural Science Foundation of Hubei Province (No. 2022CFB456) and The Research Fund of Jianghan University (No. 08210011).

Supplementary data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, J., Zhao, Y., Gong, Xk. et al. P25/CDK5-mediated Tau Hyperphosphorylation in Both Ipsilateral and Contralateral Cerebra Contributes to Cognitive Deficits in Post-stroke Mice. CURR MED SCI 43, 1084–1095 (2023). https://doi.org/10.1007/s11596-023-2792-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11596-023-2792-8

Key words

Search

Navigation