Skip to main content

Advertisement

SpringerLink
Log in

Hypoxia Increases Aβ-Induced Tau Phosphorylation by Calpain and Promotes Behavioral Consequences in AD Transgenic Mice

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Chronic hypoxia has been reported to contribute to the development of Alzheimer’s disease (AD). However, the mechanism of hypoxia in the pathogenesis of AD remains unclear. The purpose of this study was to investigate the effects of chronic hypoxia treatment on β-amyloid, tau pathologies, and the behavioral consequences in the double transgenic (APP/PS1) mice. Double transgenic mice (APP/PS1 mice) were treated with hypoxia, and spatial learning and memory abilities of mice were assessed in the Morris water maze. β-amyloid level and plaque level in APP/PS1 double transgenic mice were detected by immunohistochemistry. Protein tau, p35/p25, cyclin-dependent kinase 5 (CDK5), and calpain were detected by western blotting analysis. Chronic hypoxia treatment decreased memory and cognitive function in AD mice. In addition, chronic hypoxia treatment resulted in increased senile plaques, accompanying with increased tau phosphorylation. The hypoxia-induced increase in the tau phosphorylation was associated with a significant increase in the production of p35 and p25 and upregulation of calpain, suggesting that hypoxia induced aberrant CDK5/p25 activation via upregulation of calpain. Our results showed that chronic hypoxia exposure accelerates not only amyloid pathology but also tau pathology via calpain-mediated tau hyperphosphorylation in an AD mouse model. These pathological changes possibly contribute to the hypoxia-induced behavioral change in AD mice.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Adhami F, Liao G, Morozov YM, Schloemer A, Schmithorst VJ, Lorenz JN, Dunn RS, Vorhees CV, Wills-Karp M, Degen JL, Davis RJ, Mizushima N, Rakic P, Dardzinski BJ, Holland SK, Sharp FR, Kuan CY (2006) Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. Am J Pathol 169(2):566–583

    Article  PubMed  CAS  Google Scholar 

  • Alvarez A, Munoz JP, Maccioni RB (2001) A CDK5-p35 stable complex is involved in the beta-amyloid-induced deregulation of CDK5 activity in hippocampal neurons. Exp Cell Res 264(2):266–274

    Article  PubMed  CAS  Google Scholar 

  • Ballabh P, Braun A, Nedergaard M (2004) The blood–brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 16(1):1–13

    Article  PubMed  CAS  Google Scholar 

  • Bazan NG, Palacios-Pelaez R, Lukiw WJ (2002) Hypoxia signaling to genes: significance in Alzheimer’s disease. Mol Neurobiol 26(2–3):283–298

    Article  PubMed  CAS  Google Scholar 

  • Borenstein AR, Wu Y, Mortimer JA, Schellenberg GD, McCormick WC, Bowen JD, McCurry S, Larson EB (2005) Developmental and vascular risk factors for Alzheimer’s disease. Neurobiol Aging 26(3):325–334

    Article  PubMed  CAS  Google Scholar 

  • Bossy-Wetzel E, Schwarzenbacher R, Lipton SA (2004) Molecular pathways to neurodegeneration. Nat Med 10(Suppl):S2–S9

    Article  PubMed  Google Scholar 

  • Busciglio J, Lorenzo A, Yankner BA (1995) Beta-myloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 14(4):879–888

    Article  PubMed  CAS  Google Scholar 

  • Cancino GI, Perez de Arce K, Castro PU, Toledo EM, von Bernhardi R, Alvarez AR (2009) c-Abl tyrosine kinase modulates tau pathology and CDK5 phosphorylation in AD transgenic mice. Neurobiol Aging 32(7):1249–1261

    Article  PubMed  Google Scholar 

  • Chaudhary P, Suryakumar G, Prasad R, Singh SN, Ali S, Liavazhagan G (2012) Chronic hypobaric hypoxia mediated skeletal muscle atrophy: role of ubiquitin-proteasome pathway and calpains. Mol Cell Biochem 364(1–2):101–113

    Article  PubMed  CAS  Google Scholar 

  • Chen X, Huang T, Zhang J, Song J, Chen L, Zhu Y (2008) Involvement of calpain and p25 of CDK5 pathway in ginsenoside Rb1’s attenuation of beta-amyloid peptide25-35-induced tau hyperphosphorylation in cortical neurons. Brain Res 1200:99–106

    Article  PubMed  CAS  Google Scholar 

  • Engmann O, Giese KP (2009) Crosstalk between CDK5 and GSK3beta: implications for Alzheimer’s disease. Front Mol Neurosci 2:2

    Article  PubMed  Google Scholar 

  • Grammer M, Li D, Arunthavasothy N, Lipski J (2008) Contribution of calpain activation to early stages of hippocampal damage during oxygen–glucose deprivation. Brain Res 1196:121–130

    Article  PubMed  CAS  Google Scholar 

  • Higuchi M, Iwata N, Matsuba Y, Takano J, Suemoto T, Maeda J, Ji B, Ono M, Staufenbiel M, Suhara T, Saido TC (2012) Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology. FASEB J 26(3):1204–1217

    Article  PubMed  CAS  Google Scholar 

  • Iqbal K, Alonso AC, Chen S, Chohan MO, EI-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Igbal I (2005) Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 1739(2–3):198–210

    PubMed  CAS  Google Scholar 

  • Iqbal K, Grundke-Iqbal I (2006) Discoveries of tau, abnormally hyperphosphorylated tau and others of neurofibrillary degeneration: a personal historical perspective. J Alzheimers Dis 9(3 Suppl):219–242

    PubMed  CAS  Google Scholar 

  • Kim MJ, Oh SJ, Park SH, Kang HJ, Won MH, Kang TC, Hwang IK, Park JB, Kim JI, Kim J, Lee JY (2007) Hypoxia-induced cell death of HepG2 cells involves a necrotic cell death mediated by calpain. Apoptosis 12(4):707–718

    Article  PubMed  Google Scholar 

  • Kitazawa M, Cheng D, Laferla FM (2009) Chronic copper exposure exacerbates both amyloid and tau pathology and selectively dysregulates CDK5 in a mouse model of AD. J Neurochem 108(6):1550–1560

    Article  PubMed  CAS  Google Scholar 

  • Koh SH, Noh MY, Kim SH (2008) Amyloid-beta-induced neurotoxicity is reduced by inhibition of glycogen synthase kinase-3. Brain Res 1188:254–262

    Article  PubMed  CAS  Google Scholar 

  • Lahiri DK, Maloney B, Basha MR, Ge YW, Zawia NH (2007) How and when environmental agents and dietary factors affect the course of Alzheimer’s disease: the “LEARn” model (latent early-life associated regulation) may explain the triggering of AD. Curr Alzheimer Res 4(2):219–228

    Article  PubMed  CAS  Google Scholar 

  • Lee VM, Balin BJ, Otvos L, Trojanowski JQ (1991) A68: a major subunit of paired helical filaments and derivatized forms of normal tau. Science 251(4994):675–678

    Article  PubMed  CAS  Google Scholar 

  • Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405(6784):360–364

    Article  PubMed  CAS  Google Scholar 

  • Li L, Zhang X, Yang D, Luo G, Chen S, Le W (2009) Hypoxia increases Abeta generation by altering beta- and gamma-cleavage of APP. Neurobiol Aging 30(7):1091–1098

    Article  PubMed  CAS  Google Scholar 

  • Lipton P (1999) Ischemic cell death in brain neurons. Physiol Rev 79(4):1431–1568

    PubMed  CAS  Google Scholar 

  • Lopes JP, Oliveira CR, Agostinho P (2010) Neurodegeneration in an Abeta-induced model of Alzheimer’s disease: the role of CDK5. Aging Cell 9(1):64–77

    Article  PubMed  CAS  Google Scholar 

  • Mandelkow EM, Biernat J, Drewes G, Steiner B, Lichtenberg-Kraag B, White H, Gustke N, Mandelkow E (1993) Microtubule-associated protein tau, paired helical filaments, and phosphorylation. Ann N Y Acad Sci 695:209–216

    Article  PubMed  CAS  Google Scholar 

  • Manukhina EB, Goryacheva AV, Barskov IV, Viktorov IV, Guseva AA, Pshennikova MG, Khomenko IP, Mashina SY, Pokidyshev DA, Malyshev IY (2010) Prevention of neurodegenerative damage to the brain in rats in experimental Alzheimer’s disease by adaptation to hypoxia. Neurosci Behav Physiol 40(7):737–743

    Article  PubMed  CAS  Google Scholar 

  • Martins IJ, Hone E, Foster JK, Gnjec A, Fuller SJ, Nolan D, Gandy SE (2006) Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer’s disease and cardiovascular disease. Mol Psychiatry 11(8):721–736

    Article  PubMed  CAS  Google Scholar 

  • Masliah E, Sisk A, Mallory M, Games D (2001) Neurofibrillary pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. J Neuropathol Exp Neurol 60(4):357–368

    PubMed  CAS  Google Scholar 

  • Mazanetz MP, Fischer PM (2007) Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases. Nat Rev Drug Discov 6(6):464–479

    Article  PubMed  CAS  Google Scholar 

  • McManus T, Sadqrove M, Pringle AK, Chad JE, Sundstrom LE (2004) Intraischaemic hypothermia reduces free radical production and protects against ischaemic insults in cultured hippocampal slices. J Neurochem 91(2):327–336

    Article  PubMed  CAS  Google Scholar 

  • Monje ML, Chatten-Brown J, Hye SE, Raley-Suman KM (2000) Free radicals are involved in the damage to protein synthesis after anoxia/aglycemia and NMDA exposure. Brain Res 857(1–2):172–182

    Article  PubMed  CAS  Google Scholar 

  • Morais LH, Lima MMS, Martynhak BJ, Santiago R, Takahashi TT, Ariza D, Barbiero JK, Andreatini R, Vital MABF (2012) Characterization of motor, depressive-like and neurochemical alterations induced by a short-term rotenone administration. Pharmacol Rep 64:1081–1090

    PubMed  CAS  Google Scholar 

  • Newcomb-Fernandez JK, Zhao X, Pike BR, Wang KK, Kampfl A, Beer R, DeFord SM, Hayes RL (2001) Concurrent assessment of calpain and caspase-3 activation after oxygen-glucose deprivation in primary septo-hippocampal cultures. J Cereb Blood Flow Metab 21(11):1281–1294

    Article  PubMed  CAS  Google Scholar 

  • Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH (1999) Conversion of p35 to p25 deregulates CDK5 activity and promotes neurodegeneration. Nature 402(6762):615–622

    Article  PubMed  CAS  Google Scholar 

  • Picconi B, Tortiglione A, Barone I, Centonze D, Gardoni F, Gubellini P, Bonsi P, Pisani A, Bernardi G, Di Luca M, Calabresi P (2006) NR2B subunit exerts a critical role in postischemic synaptic plasticity. Stroke 37(7):1895–1901

    Article  PubMed  Google Scholar 

  • Roberts-Lewis JM, Savage MJ, Marcy VR, Pinsker LR, Siman R (1994) Immunolocalization of calpain I-mediated spectrin degradation to vulnerable neurons in the ischemic gerbil brain. J Neurosci 14(6):3934–3944

    PubMed  CAS  Google Scholar 

  • Sato S, Xu J, Okuyama S, Martinez LB, Walsh SM, Jacobsen MT, Swan RJ, Schlautman JD, Ciborowski P, Ikezu T (2008) Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1. J Neurosci 28(53):14511–14521

    Article  PubMed  CAS  Google Scholar 

  • Shewale PB, Patil RA, Hiray YA (2012) Antidepressant-like activity of anthocyanidins from Hibscus rosa-sinensis flowers in tail suspension test and forced swim test. Indian J Pharmacol 44(4):454–457

    Article  PubMed  CAS  Google Scholar 

  • Skoog I, Gustafson D (2006) Update on hypertension and Alzheimer’s disease. Neurol Res 28(6):605–611

    Article  PubMed  Google Scholar 

  • Toescu E, Verkhratsky A (2004) Ca2+ and mitochondria as substrates for deficits in synaptic plasticity in normal brain ageing. J Cell Mol Med 8(2):181–190

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Zheng W, Xei JW, Wang T, Wang SL, Teng WP, Wang ZY (2010) Insulin deficiency exacerbates cerebral amyloidosis and behavioral deficits in an Alzheimer transgenic mouse model. Mol Neurodegener 5:46

    Article  PubMed  Google Scholar 

  • Zheng W, Xin N, Chi ZH, Zhao BL, Zhang J, Li JY, Wang ZY (2009) Divalent metal transporter 1 is involved in amyloid precursor protein processing and Abeta generation. FASEB J 23(12):4207–4217

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, The 4th Affiliated Hospital of China Medical University, Shenyang, 110032, China

    Lianbo Gao, Shen Tian, Honghua Gao & Yanyuan Xu

Authors
  1. Lianbo Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shen Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Honghua Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yanyuan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lianbo Gao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gao, L., Tian, S., Gao, H. et al. Hypoxia Increases Aβ-Induced Tau Phosphorylation by Calpain and Promotes Behavioral Consequences in AD Transgenic Mice. J Mol Neurosci 51, 138–147 (2013). https://doi.org/10.1007/s12031-013-9966-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-013-9966-y

Keywords

Search

Navigation