A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice

Varsha Shukla, Ya Li Zheng, Santosh K. Mishra, Niranjana D. Amin, Joseph Steiner, Philip Grant, Sashi Kesavapany, Harish C. Pant

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)174-186
Number of pages13
JournalFASEB Journal
Volume27
Issue number1
DOIs
StatePublished - Jan 2013
Externally publishedYes

Fingerprint

Cyclin-Dependent Kinase 5
Alzheimer Disease
Phenotype
Peptides
Pathology
Neurofibrillary Tangles
Amyloid Plaques
Amyloid
Poisons
Cell death
Intraperitoneal Injections
Blood-Brain Barrier
Neurodegenerative Diseases
Toxicity
Brain
Cell Cycle
Cell Death
Phosphotransferases
Therapeutics
Cells

Keywords

  • Cdk5 hyperphosphorylation
  • Neurodegeneration
  • Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Shukla, V., Zheng, Y. L., Mishra, S. K., Amin, N. D., Steiner, J., Grant, P., ... Pant, H. C. (2013). A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice. FASEB Journal, 27(1), 174-186. https://doi.org/10.1096/fj.12-217497

A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice. / Shukla, Varsha; Zheng, Ya Li; Mishra, Santosh K.; Amin, Niranjana D.; Steiner, Joseph; Grant, Philip; Kesavapany, Sashi; Pant, Harish C.

In: FASEB Journal, Vol. 27, No. 1, 01.2013, p. 174-186.

Research output: Contribution to journalArticle

Shukla, V, Zheng, YL, Mishra, SK, Amin, ND, Steiner, J, Grant, P, Kesavapany, S & Pant, HC 2013, 'A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice', FASEB Journal, vol. 27, no. 1, pp. 174-186. https://doi.org/10.1096/fj.12-217497
Shukla, Varsha ; Zheng, Ya Li ; Mishra, Santosh K. ; Amin, Niranjana D. ; Steiner, Joseph ; Grant, Philip ; Kesavapany, Sashi ; Pant, Harish C. / A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice. In: FASEB Journal. 2013 ; Vol. 27, No. 1. pp. 174-186.
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