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A Cdk5 inhibitory peptide reduces tau hyperphosphorylation and apoptosis in neurons
Author(s) -
Zheng YaLi,
Kesavapany Sashi,
Gravell Maneth,
Hamilton Rebecca S,
Schubert Manfred,
Amin Niranjana,
Albers Wayne,
Grant Philip,
Pant Harish C
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600441
Subject(s) - cyclin dependent kinase 5 , biology , hyperphosphorylation , kinase , microbiology and biotechnology , activator (genetics) , extracellular , phosphorylation , tau protein , cyclin dependent kinase , cyclin dependent kinase 6 , epitope , intracellular , neurodegeneration , apoptosis , alzheimer's disease , cyclin dependent kinase 2 , biochemistry , protein kinase a , immunology , cell cycle , receptor , disease , medicine , antigen
The extracellular aggregation of amyloid β (Aβ) 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 Aβ 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, Aβ 1−42 ‐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.