Document Detail


A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice.
MedLine Citation:
PMID:  23038754     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Varsha Shukla; Ya-Li Zheng; Santosh K Mishra; Niranjana D Amin; Joseph Steiner; Philip Grant; Sashi Kesavapany; Harish C Pant
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2012-10-04
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  27     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-03     Completed Date:  2013-03-07     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  174-86     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Alzheimer Disease / prevention & control*
Amino Acid Sequence
Animals
Apoptosis
Enzyme Activators / pharmacology*
Mice
Mice, Transgenic
Molecular Sequence Data
Nerve Tissue Proteins / chemistry,  pharmacology*
Phosphorylation
Chemical
Reg. No./Substance:
0/Enzyme Activators; 0/Nerve Tissue Proteins; 0/neuronal Cdk5 activator (p25-p35)
Comments/Corrections

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