International Conference on Brain Disorders and Therapeutics
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Title: A novel approach to prevent Alzheimer’s, Parkinson’s and ALS diseases phenotypes in situ and in transgenic mice models using a small peptide derived from cyclin - dependent kinase 5 (Cdk5) neuron specific activator protein, p35
Biography: Harish C. Pant
Besides the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs), it has been now well documented thatrncyclin-dependent kinase 5 (Cdk5), a critical neuronal kinase in nervous system development, function and survival whenrnderegulated and hyperactivated induces AD and ALS like phenotypes in mice. Under physiological conditions, Cdk5 activity isrntightly regulated. The deregulation and hyperactivation of Cdk5/p25 due to neuronal insults and toxicity induces neuropathology.rnThus Cdk5/p25 becomes prime therapeutic target for AD and other neurodegenerative diseases associated with the hyperactivationrnof Cdk5. In order to prevent hyperactivation of Cdk5/p25, we have designed several small peptides of p25 on the basis of Cdk5/rnp25 crystal structure and molecular modeling, evaluated for competition with p25 and thus inhibiting selectively the hyperactivityrnof Cdk5. We discovered a small peptide (p5) comprising of 24 amino acids inhibited Cdk5 hyperactivation. The modified of p5rnto TFP5 crosses blood brain barrier (BBB) and was examined its therapeutic role in transgenic AD and ALS model mice. The p25rntransgenic AD model (p25Tg) and 5XFAD mice were chosen since these mice show similar phenotypes to AD patients. Post TFP5rninjections in p25Tg mice, 5XFAD and ALS model mice displayed significant reduction in Cdk5/p25 hyperactivity, Aβ plaquernformation along with behavioral rescue. TFP5 does not inhibit normal Cdk5/p35 activity and therefore has no toxic side effects.rnIn addition, treated mice rescued synaptic dysfunction, neuroinflammation and a reduction in phospho-neurofilaments/tau andrnneuronal cell death. These results indicate that TFP5 has a potential role as a therapeutic candidate for AD, ALS and other relatedrnneurological diseases.