title: Specific inhibition of p25/Cdk5 activity by the Cdk5 inhibitory peptide reduces neurodegeneration in vivo.
abstract: 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 death in vitro and in 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 hyperactivation in 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.
authors.affiliation: Department of Biochemistry, Centre for Life Sciences, National University of Singapore, 28 Medical Drive, #04-21, Singapore 117456.
authors.forename: Jeyapriya Raja
authors.initials: JR
authors.lastname: Sundaram
authors.forename: Charlene Priscilla
authors.initials: CP
authors.lastname: Poore
authors.forename: Noor Hazim Bin
authors.initials: NH
authors.lastname: Sulaimee
authors.forename: Tej
authors.initials: T
authors.lastname: Pareek
authors.forename: A B M A
authors.initials: AB
authors.lastname: Asad
authors.forename: Ramamoorthy
authors.initials: R
authors.lastname: Rajkumar
authors.forename: Wei Fun
authors.initials: WF
authors.lastname: Cheong
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.forename: Gavin Stewart
authors.initials: GS
authors.lastname: Dawe
authors.forename: Kai-Hsiang
authors.initials: KH
authors.lastname: Chuang
authors.forename: Harish C
authors.initials: HC
authors.lastname: Pant
authors.forename: Sashi
authors.initials: S
authors.lastname: Kesavapany
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001284:Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics* / Q000378:metabolism; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism
chemical_list: D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5