Specific Inhibition of p25/Cdk5 Activity by the Cdk5 Inhibitory Peptide Reduces NeurodegenerationIn Vivo
| Autor: | Gavin S. Dawe, Wei Fun Cheong, A.B.M.A. Asad, Harish C. Pant, Sashi Kesavapany, Charlene Priscilla Poore, Markus R Wenk, Noor Hazim Bin Sulaimee, Jeyapriya R. Sundaram, Tej K. Pareek, Ramamoorthy Rajkumar, Kai-Hsiang Chuang |
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| Rok vydání: | 2013 |
| Předmět: |
Genetically modified mouse
Apoptosis Mice Transgenic tau Proteins Biology Mice medicine Animals Phosphorylation Cognitive decline Neuroinflammation Cyclin-Dependent Kinase Inhibitor Proteins Neurons Behavior Animal Hyperactivation Activator (genetics) General Neuroscience Cyclin-dependent kinase 5 Neurodegeneration Brain Cyclin-Dependent Kinase 5 Calpain Articles medicine.disease female genital diseases and pregnancy complications eye diseases Cell biology Memory Short-Term nervous system Nerve Degeneration biology.protein Atrophy Neuroscience |
| Zdroj: | The Journal of Neuroscience. 33:334-343 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.3593-12.2013 |
| Popis: | The aberrant hyperactivation of Cyclin-dependent kinase 5 (Cdk5), by the production of its truncated activator p25, results in the formation of hyperphosphorylated tau, neuroinflammation, amyloid deposition, and neuronal deathin vitroandin vivo. Mechanistically, this occurs as a result of a neurotoxic insult that invokes the intracellular elevation of calcium to activate calpain, which cleaves the Cdk5 activator p35 into p25. It has been shown previously that the p25 transgenic mouse as a model to investigate the mechanistic implications of p25 production in the brain, which recapitulates deregulated Cdk5-mediated neuropathological changes, such as hyperphosphorylated tau and neuronal death. To date, strategies to inhibit Cdk5 activity have not been successful in targeting selectively aberrant activity without affecting normal Cdk5 activity. Here we show that the selective inhibition of p25/Cdk5 hyperactivationin vivo, through overexpression of the Cdk5 inhibitory peptide (CIP), rescues against the neurodegenerative pathologies caused by p25/Cdk5 hyperactivation without affecting normal neurodevelopment afforded by normal p35/Cdk5 activity. Tau and amyloid pathologies as well as neuroinflammation are significantly reduced in the CIP–p25 tetra transgenic mice, whereas brain atrophy and subsequent cognitive decline are reversed in these mice. The findings reported here represent an important breakthrough in elucidating approaches to selectively inhibit the p25/Cdk5 hyperactivation as a potential therapeutic target to reduce neurodegeneration. |
| Databáze: | OpenAIRE |
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