Skip to main content

Advertisement

Log in

PHF-like tau phosphorylation in mammalian hibernation is not associated with p25-formation

  • Dementias - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

In Alzheimer’s disease and related disorders, hyperphosphorylation of tau is associated with an increased activity of cyclin dependent kinase 5 (cdk5). Elevated cdk5 activity is thought to be due to the formation of p25 and thereby represents a critical element in the dysregulation of tau phosphorylation under pathological conditions. However, there is still a controversy regarding the correlation of p25 generation and tau pathology. Recently, we demonstrated physiological, paired helical filament-like tau phosphorylation that reversibly occurs in hibernating mammals. Here we used this model to test whether the tau phosphorylation in hibernation is associated with the formation of p25. Analysing brain material of arctic ground squirrels and Syrian hamsters we found no evidence for a hibernation dependent generation of p25. Hence, we suppose that phosphorylation of tau does not require the formation of p25. Instead we suggest that the truncation of p35 to p25 represents a characteristic of pathological alterations and may contribute to aggregation and deposition of hyperphosphorylated tau.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Arendt T, Stieler J, Strijkstra AM et al (2003) Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci 23:6972–6981

    PubMed  CAS  Google Scholar 

  • Barnes BM (1989) Freeze avoidance in a mammal: body temperatures below 0°C in an Arctic hibernator. Science 244:1593–1595

    Article  PubMed  CAS  Google Scholar 

  • Baumann K, Mandelkow EM, Biernat J et al (1993) Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. FEBS Lett 336:417–424

    Article  PubMed  CAS  Google Scholar 

  • Biernat J, Gustke N, Drewes G et al (1993) Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron 11:153–163

    Article  PubMed  CAS  Google Scholar 

  • Binder LI, Frankfurter A, Rebhun LI (1985) The distribution of tau in the mammalian central nervous system. J.Cell Biol 101:1371–1378

    Article  PubMed  CAS  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  • Bramblett GT, Goedert M, Jakes R et al (1993) Abnormal tau phosphorylation at Ser396 in Alzheimer’s disease recapitulates development and contributes to reduced microtubule binding. Neuron 10:1089–1099

    Article  PubMed  CAS  Google Scholar 

  • Camins A, Verdaguer E, Folch J et al (2006) The role of CDK5/P25 formation/inhibition in neurodegeneration. Drug News Perspect 19:453–460

    Article  PubMed  CAS  Google Scholar 

  • Chae T, Kwon YT, Bronson R et al (1997) Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 18:29–42

    Article  PubMed  CAS  Google Scholar 

  • Cleveland DW, Hwo SY, Kirschner MW (1977) Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. J Mol Biol 116:227–247

    Article  PubMed  CAS  Google Scholar 

  • Cruz JC, Tsai LH (2004) Cdk5 deregulation in the pathogenesis of Alzheimer’s disease. Trends Mol Med 10:452–458

    Article  PubMed  CAS  Google Scholar 

  • Dhariwala FA, Rajadhyaksha MS (2008) An unusual member of the Cdk family: Cdk5. Cell Mol Neurobiol 28:351–369

    Article  PubMed  CAS  Google Scholar 

  • Drewes G, Lichtenberg-Kraag B, Doring F et al (1992) Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state. EMBO J 11:2131–2138

    PubMed  CAS  Google Scholar 

  • Fischer A, Sananbenesi F, Spiess J et al (2003) Cdk5: a novel role in learning and memory. Neurosignals 12:200–208

    Article  PubMed  CAS  Google Scholar 

  • Fischer A, Sananbenesi F, Pang PT et al (2005) Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48:825–838

    Article  PubMed  CAS  Google Scholar 

  • Floyd SR, Porro EB, Slepnev VI et al (2001) Amphiphysin 1 binds the cyclin-dependent kinase (cdk) 5 regulatory subunit p35 and is phosphorylated by cdk5 and cdc2. J Biol Chem 276:8104–8110

    Article  PubMed  CAS  Google Scholar 

  • Giese KP, Ris L, Plattner F (2005) Is there a role of the cyclin-dependent kinase 5 activator p25 in Alzheimer’s disease? NeuroReport 16:1725–1730

    Article  PubMed  CAS  Google Scholar 

  • Goedert M, Spillantini MG, Cairns NJ et al (1992) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8:159–168

    Article  PubMed  CAS  Google Scholar 

  • Goedert M, Hasegawa M, Jakes R et al (1997) Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. FEBS Lett 409:57–62

    Article  PubMed  CAS  Google Scholar 

  • Härtig W, Stieler J, Boerema AS et al (2007) Hibernation model of tau phosphorylation in hamsters: selective vulnerability of cholinergic basal forebrain neurons—implications for Alzheimer’s disease. Eur J NeuroSci 25:69–80

    Article  PubMed  Google Scholar 

  • Heldmaier G, Ortmann S, Elvert R (2004) Natural hypometabolism during hibernation and daily torpor in mammals. Respir Physiol Neurobiol 141:317–329

    Article  PubMed  Google Scholar 

  • Hisanaga S, Saito T (2003) The regulation of cyclin-dependent kinase 5 activity through the metabolism of p35 or p39 Cdk5 activator. Neurosignals 12:221–229

    Article  PubMed  CAS  Google Scholar 

  • Ishiguro K, Ihara Y, Uchida T et al (1988) A novel tubulin-dependent protein kinase forming a paired helical filament epitope on tau. J Biochem (Tokyo) 104:319–321

    CAS  Google Scholar 

  • Ishiguro K, Shiratsuchi A, Sato S et al (1993) Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett 325:167–172

    Article  PubMed  CAS  Google Scholar 

  • Kamei H, Saito T, Ozawa M et al (2007) Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25 by site-specific phosphorylation. J Biol Chem 282:1687–1694

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi S, Ishiguro K, Omori A et al (1993) A cdc2-related kinase PSSALRE/cdk5 is homologous with the 30 kDa subunit of tau protein kinase II, a proline-directed protein kinase associated with microtubule. FEBS Lett 335:171–175

    Article  PubMed  CAS  Google Scholar 

  • Lee MS, Kwon YT, Li M et al (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405:360–364

    Article  PubMed  CAS  Google Scholar 

  • Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159

    Article  PubMed  CAS  Google Scholar 

  • Lew J, Qi Z, Huang QQ et al (1995) Structure, function, and regulation of neuronal Cdc2-like protein kinase. Neurobiol Aging 16:263–268

    Article  PubMed  CAS  Google Scholar 

  • Li T, Hawkes C, Qureshi HY et al (2006) Cyclin-dependent protein kinase 5 primes microtubule-associated protein tau site-specifically for glycogen synthase kinase 3 beta. Biochemistry 45:3134–3145

    Article  PubMed  CAS  Google Scholar 

  • Long RA, Hut RA, Barnes BM (2007) Simultaneous collection of body temperature and activity data in burrowing mammals: a new technique. J Wildl Manage 71:1375–1379

    Article  Google Scholar 

  • Nikolic M, Dudek H, Kwon YT et al (1996) The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation. Genes Dev 10:816–825

    Article  PubMed  CAS  Google Scholar 

  • Noble W, Olm V, Takata K et al (2003) Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38:555–565

    Article  PubMed  CAS  Google Scholar 

  • Ohshima T, Ward JM, Huh CG et al (1996) Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Natl Acad Sci USA 93:11173–11178

    Article  PubMed  CAS  Google Scholar 

  • Oklejewicz M, Daan S, Strijkstra AM (2001) Temporal organisation of hibernation in wild-type and tau mutant Syrian hamsters. J Comp Physiol [B] 171:431–439

    CAS  Google Scholar 

  • Paglini G, Pigino G, Kunda P et al (1998) Evidence for the participation of the neuron-specific CDK5 activator P35 during laminin-enhanced axonal growth. J Neurosci 18:9858–9869

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Patrick GN, Zukerberg L, Nikolic M et al (2001) Reply: Neurobiology p25 protein in neurodegeneration. Nature 411:764–765

    Article  PubMed  Google Scholar 

  • Reynolds CH, Utton MA, Gibb GM et al (1997) Stress-activated protein kinase/c-jun N-terminal kinase phosphorylates tau protein. J Neurochem 68:1736–1744

    Article  PubMed  CAS  Google Scholar 

  • Samsonov A, Yu JZ, Rasenick M et al (2004) Tau interaction with microtubules in vivo. J Cell Sci 117:6129–6141

    Article  PubMed  CAS  Google Scholar 

  • Stieler JT, Boerema AS, Bullmann T et al. (2008) In: Lovegrove BG, McKechnie AE (ed) Hypometabolism in animals: torpor, hibernation and cryobiology, vol. 1. University of KwaZulu-Natal, Pietermaritzburg, pp 133–142

  • Su B, Wang X, Drew KL et al (2008) Physiological regulation of tau phosphorylation during hibernation. J Neurochem 105:2098–2108

    Article  CAS  PubMed  Google Scholar 

  • Tandon A, Yu H, Wang L et al (2003) Brain levels of CDK5 activator p25 are not increased in Alzheimer’s or other neurodegenerative diseases with neurofibrillary tangles. J Neurochem 86:572–581

    Article  PubMed  CAS  Google Scholar 

  • Tseng HC, Zhou Y, Shen Y et al (2002) A survey of Cdk5 activator p35 and p25 levels in Alzheimer’s disease brains. FEBS Lett 523:58–62

    Article  PubMed  CAS  Google Scholar 

  • Ueda S, Ibuka N (1995) An analysis of factors that induce hibernation in Syrian hamsters. Physiol Behav 58:653–657

    Article  PubMed  CAS  Google Scholar 

  • Yoo BC, Lubec G (2001) p25 protein in neurodegeneration. Nature 411:763–764

    Article  PubMed  CAS  Google Scholar 

  • Zheng-Fischhofer Q, Biernat J, Mandelkow EM et al (1998) Sequential phosphorylation of Tau by glycogen synthase kinase-3 beta and protein kinase A at Thr212 and Ser214 generates the Alzheimer-specific epitope of antibody AT100 and requires a paired-helical-filament-like conformation. Eur J Biochem 252:542–552

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Sabine Seifert for technical assistance. This study was supported by grants from the US Army Medical Research and Materiel Command (Proposal No. 05178001) and the NSF (0076039) to B.M. Barnes.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jens Thorsten Stieler.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stieler, J.T., Bullmann, T., Kohl, F. et al. PHF-like tau phosphorylation in mammalian hibernation is not associated with p25-formation. J Neural Transm 116, 345–350 (2009). https://doi.org/10.1007/s00702-008-0181-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-008-0181-x

Keywords

Navigation