title: A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice.
abstract: Alzheimer's disease (AD), one of the leading neurodegenerative disorders of older adults, which causes major socioeconomic burdens globally, lacks effective therapeutics without significant side effects. Besides the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs), it has been reported that cyclin-dependent kinase 5 (Cdk5), a critical neuronal kinase, is hyperactivated in AD brains and is, in part, responsible for the above pathology. Here we show that a modified truncated 24-aa peptide (TFP5), derived from the Cdk5 activator p35, penetrates the blood-brain barrier after intraperitoneal injections, inhibits abnormal Cdk5 hyperactivity, and significantly rescues AD pathology (up to 70-80%) in 5XFAD AD model mice. The mutant mice, injected with TFP5 exhibit behavioral rescue, whereas no rescue was observed in mutant mice injected with either saline or scrambled peptide. However, TFP5 does not inhibit cell cycle Cdks or normal Cdk5/p35 activity, and thereby has no toxic side effects (even at 200 mg/kg), a common problem in most current therapeutics for AD. In addition, treated mice displayed decreased inflammation, amyloid plaques, NFTs, cell death, and an extended life by 2 mo. These results suggest TFP5 as a potential therapeutic, toxicity-free candidate for AD.
authors.affiliation: Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Varsha
authors.initials: V
authors.lastname: Shukla
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Zheng
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Mishra
authors.forename: Niranjana D
authors.initials: ND
authors.lastname: Amin
authors.forename: Joseph
authors.initials: J
authors.lastname: Steiner
authors.forename: Philip
authors.initials: P
authors.lastname: Grant
authors.forename: Sashi
authors.initials: S
authors.lastname: Kesavapany
authors.forename: Harish C
authors.initials: HC
authors.lastname: Pant
mesh_terms: D000544:Alzheimer Disease / Q000517:prevention & control*; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D020536:Enzyme Activators / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation
chemical_list: D020536:Enzyme Activators; D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35)