| A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice. | |
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MedLine Citation:
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PMID: 23038754 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Intramural Date: 2012-10-04 |
Journal Detail:
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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:
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Created Date: 2013-01-03 Completed Date: 2013-03-07 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 8804484 Medline TA: FASEB J Country: United States |
Other Details:
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Languages: eng Pagination: 174-86 Citation Subset: IM |
Affiliation:
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Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alzheimer Disease
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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:
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0/Enzyme Activators; 0/Nerve Tissue Proteins; 0/neuronal Cdk5 activator (p25-p35) |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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