Silencing of CDK5 reduces neurofibrillary tangles in transgenic Alzheimer's mice

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 (3Tg-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.

• Autores: Piedrahita, Diego; Hernández, Israel; López Tobón, Alejandro; Gallego Gómez, Juan Carlos; Cardona Gómez, Gloria Patricia; Fedorov, Dmitry; Obara, Boguslaw; Manjunath, B.S.; Boudreau, Ryan L.; LaFerla, Frank; Kosik, Kenneth S.
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2010
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/47814
• Acceso en línea: https://hdl.handle.net/10495/47814
• Palabra clave: 610 - Medicina y salud; Enfermedad de Alzheimer; Alzheimer Disease; Anticuerpos Monoclonales; Antibodies, Monoclonal; Western Blotting; Blotting, Western; Región CA1 Hipocampal; CA1 Region, Hippocampal; Técnica del Anticuerpo Fluorescente; Fluorescent Antibody Technique; Silenciador del Gen; Gene Silencing; Inmunohistoquímica; Immunohistochemistry; Ratones Endogámicos C57BL; Mice, Inbred C57BL; Ratones Transgénicos; Mice, Transgenic; Ovillos Neurofibrilares; Neurofibrillary Tangles; Proteínas tau; tau Proteins; https://id.nlm.nih.gov/mesh/D000544; https://id.nlm.nih.gov/mesh/D000911; https://id.nlm.nih.gov/mesh/D015153; https://id.nlm.nih.gov/mesh/D056547; https://id.nlm.nih.gov/mesh/D005455; https://id.nlm.nih.gov/mesh/D020868; https://id.nlm.nih.gov/mesh/D007150; https://id.nlm.nih.gov/mesh/D008810; https://id.nlm.nih.gov/mesh/D008822; https://id.nlm.nih.gov/mesh/D016874; https://id.nlm.nih.gov/mesh/D016875; ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades
• Rights: openAccess
• License: http://creativecommons.org/licenses/by/4.0/