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  • The EMBO Journal (2005) 24, 209 - 220
  • doi:10.1038/sj.emboj.7600441

Published online: 9 December 2004

A Cdk5 inhibitory peptide reduces tau hyperphosphorylation and apoptosis in neurons

Ya-Li Zheng1,a, Sashi Kesavapany1,a, Maneth Gravell2, Rebecca S Hamilton2, Manfred Schubert2, Niranjana Amin1, Wayne Albers1, Philip Grant1 and Harish C Pant1

  1. Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
  2. Laboratory of Molecular Virology and Neurogenetics, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

Correspondence to:

Harish C Pant, Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 36, Room 4D04, 36 Convent Drive, Bethesda, MD 20892-4130, USA. Tel.: +1 301 402 2124; Fax: +1 301 496 1339; E-mail: panth@ninds.nih.gov

aThese authors contributed equally to this work

Received 6 February 2004; Accepted 20 September 2004

The extracellular aggregation of amyloid beta (Abeta) peptides and the intracellular hyperphosphorylation of tau at specific epitopes are pathological hallmarks of neurodegenerative diseases such as Alzheimer's disease (AD). Cdk5 phosphorylates tau at AD-specific phospho-epitopes when it associates with p25. p25 is a truncated activator, which is produced from the physiological Cdk5 activator p35 upon exposure to Abeta peptides. We show that neuronal infections with Cdk5 inhibitory peptide (CIP) selectively inhibit p25/Cdk5 activity and suppress the aberrant tau phosphorylation in cortical neurons. Furthermore, Abeta1-42-induced apoptosis of these cortical neurons was also reduced by coinfection with CIP. Of particular importance is our finding that CIP did not inhibit endogenous or transfected p35/Cdk5 activity, nor did it inhibit the other cyclin-dependent kinases such as Cdc2, Cdk2, Cdk4 and Cdk6. These results, therefore, provide a strategy to address, and possibly ameliorate, the pathology of neurodegenerative diseases that may be a consequence of aberrant p25 activation of Cdk5, without affecting 'normal' Cdk5 activity.

  • Keywords:

    • Alzheimer's disease,
    • Cdk5 inhibitory peptide (CIP),
    • hyperphosphorylation,
    • p25,
    • tau