Journal article
Silencing of CDK5 Reduces Neurofibrillary Tangles in Transgenic Alzheimer's Mice
The Journal of neuroscience, Vol.30(42), pp.13966-13976
10/20/2010
DOI: 10.1523/JNEUROSCI.3637-10.2010
PMCID: PMC3003593
PMID: 20962218
Abstract
Alzheimer's disease is a major cause of dementia for which treatments remain unsatisfactory. Cyclin-dependent kinase 5 (CDK5) is a relevant kinase that has been hypothesized to contribute to the tau pathology. Several classes of chemical inhibitors for CDK5 have been developed, but they generally lack the specificity to distinguish among various ATP-dependent kinases. Therefore, the efficacy of these compounds when tested in animal models cannot definitively be attributed to an effect on CDK5. However, RNA interference (RNAi) targeting of CDK5 is specific and can be used to validate CDK5 as a possible treatment target. We delivered a CDK5 RNAi by lentiviral or adenoassociated viral vectors and analyzed the results
in vitro
and
in vivo
. Silencing of CDK5 reduces the phosphorylation of tau in primary neuronal cultures and in the brain of wild-type C57BL/6 mice. Furthermore, the knockdown of CDK5 strongly decreased the number of neurofibrillary tangles in the hippocampi of triple-transgenic mice (3×Tg-AD mice). Our data suggest that this downregulation may be attributable to the reduction of the CDK5 availability in the tissue, without affecting the CDK5 kinase activity. In summary, our findings validate CDK5 as a reasonable therapeutic target for ameliorating tau pathology.
Details
- Title: Subtitle
- Silencing of CDK5 Reduces Neurofibrillary Tangles in Transgenic Alzheimer's Mice
- Creators
- Diego Piedrahita - Cellular and Molecular Neurobiology Area, Viral Vector Core and Gene Therapy, Group of Neuroscience of Antioquia, Faculty of Medicine, Sede de Investigación Universitaria, University of Antioquia, AA 1226 Medellin, ColombiaIsrael Hernández - Cellular and Molecular Neurobiology Area, Viral Vector Core and Gene Therapy, Group of Neuroscience of Antioquia, Faculty of Medicine, Sede de Investigación Universitaria, University of Antioquia, AA 1226 Medellin, ColombiaAlejandro López-Tobón - Cellular and Molecular Neurobiology Area, Viral Vector Core and Gene Therapy, Group of Neuroscience of Antioquia, Faculty of Medicine, Sede de Investigación Universitaria, University of Antioquia, AA 1226 Medellin, ColombiaDmitry Fedorov - Center for BioImage Informatics andBoguslaw Obara - Oxford e-Research Centre and Oxford Centre for Integrative Systems Biology, University of Oxford, Oxford OX1 3QG, United KingdomB. S Manjunath - Center for BioImage Informatics andRyan L Boudreau - Viral Vector Core and Davidson Laboratory, University of Iowa, Iowa City, Iowa 52242, andBeverly Davidson - Viral Vector Core and Davidson Laboratory, University of Iowa, Iowa City, Iowa 52242, andFrank LaFerla - Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, California 92697Juan Carlos Gallego-Gómez - Cellular and Molecular Neurobiology Area, Viral Vector Core and Gene Therapy, Group of Neuroscience of Antioquia, Faculty of Medicine, Sede de Investigación Universitaria, University of Antioquia, AA 1226 Medellin, ColombiaKenneth S Kosik - Neuroscience Research Institute and Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, California 93106Gloria Patricia Cardona-Gómez - Cellular and Molecular Neurobiology Area, Viral Vector Core and Gene Therapy, Group of Neuroscience of Antioquia, Faculty of Medicine, Sede de Investigación Universitaria, University of Antioquia, AA 1226 Medellin, Colombia
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.30(42), pp.13966-13976
- Publisher
- Society for Neuroscience
- DOI
- 10.1523/JNEUROSCI.3637-10.2010
- PMID
- 20962218
- PMCID
- PMC3003593
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Language
- English
- Date published
- 10/20/2010
- Academic Unit
- Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984065384502771
Metrics
13 Record Views