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 (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.
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.
Diego
D
Piedrahita
Israel
I
Hernández
Alejandro
A
López-Tobón
Dmitry
D
Fedorov
Boguslaw
B
Obara
B S
BS
Manjunath
Ryan L
RL
Boudreau
Beverly
B
Davidson
Frank
F
Laferla
Juan Carlos
JC
Gallego-Gómez
Kenneth S
KS
Kosik
Gloria Patricia
GP
Cardona-Gómez
D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal; D015153:Blotting, Western; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics* / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000235:genetics* / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D000911:Antibodies, Monoclonal; C085349:PHF-1 monoclonal antibody; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse