title: TFP5, a Peptide Inhibitor of Aberrant and Hyperactive Cdk5/p25, Attenuates Pathological Phenotypes and Restores Synaptic Function in CK-p25Tg Mice.
abstract: It has been reported that cyclin-dependent kinase 5 (cdk5), a critical neuronal kinase, is hyperactivated in Alzheimer's disease (AD) and may be, in part, responsible for the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs). It has been proposed by several laboratories that hyperactive cdk5 results from the overexpression of p25 (a truncated fragment of p35, the normal cdk5 regulator), which, when complexed to cdk5, induces hyperactivity, hyperphosphorylated tau/NFTs, amyloid-β plaques, and neuronal death. It has previously been shown that intraperitoneal (i.p.) injections of a modified truncated 24-aa peptide (TFP5), derived from the cdk5 activator p35, penetrated the blood-brain barrier and significantly rescued AD-like pathology in 5XFAD model mice. The principal pathology in the 5XFAD mutant, however, is extensive amyloid plaques; hence, as a proof of concept, we believe it is essential to demonstrate the peptide's efficacy in a mouse model expressing high levels of p25, such as the inducible CK-p25Tg model mouse that overexpresses p25 in CamKII positive neurons. Using a modified TFP5 treatment, here we show that peptide i.p. injections in these mice decrease cdk5 hyperactivity, tau, neurofilament-M/H hyperphosphorylation, and restore synaptic function and behavior (i.e., spatial working memory, motor deficit using Rota-rod). It is noteworthy that TFP5 does not inhibit endogenous cdk5/p35 activity, nor other cdks in vivo suggesting it might have no toxic side effects, and may serve as an excellent therapeutic candidate for neurodegenerative disorders expressing abnormally high brain levels of p25 and hyperactive cdk5.
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Varsha
authors.initials: V
authors.lastname: Shukla
authors.affiliation: Department of Brain and Cognitive Sciences, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Jinsoo
authors.initials: J
authors.lastname: Seo
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: B K
authors.initials: BK
authors.lastname: Binukumar
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Niranjana D
authors.initials: ND
authors.lastname: Amin
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Preethi
authors.initials: P
authors.lastname: Reddy
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Grant
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Kuntz
authors.affiliation: Singapore University, Singapore.
authors.forename: Sashi
authors.initials: S
authors.lastname: Kesavapany
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Steiner
authors.affiliation: National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MA, USA.
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Mishra
authors.affiliation: Department of Brain and Cognitive Sciences, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Harish C
authors.initials: HC
authors.lastname: Pant
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D004195:Disease Models, Animal; D004318:Doxycycline / Q000008:administration & dosage; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006948:Hyperkinesis / Q000188:drug therapy / Q000209:etiology; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D016202:N-Methylaspartate / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use*; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; C492236:Cdk5r1 protein, mouse; D018690:Excitatory Amino Acid Agonists; D010455:Peptides; C000624536:TFP5 peptide; D016875:tau Proteins; D016202:N-Methylaspartate; D010770:Phosphotransferases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004318:Doxycycline
keywords: Alzheimer’s disease; TFP5; cyclin-dependent kinase 5; hyperphosphorylation; synaptic function