title: p35 and Rac1 underlie the neuroprotection and cognitive improvement induced by CDK5 silencing.
abstract: CDK5 plays an important role in neurotransmission and synaptic plasticity in the normal function of the adult brain, and dysregulation can lead to Tau hyperphosphorylation and cognitive impairment. In a previous study, we demonstrated that RNAi knock down of CDK5 reduced the formation of neurofibrillary tangles (NFT) and prevented neuronal loss in triple transgenic Alzheimer's mice. Here, we report that CDK5 RNAi protected against glutamate-mediated excitotoxicity using primary hippocampal neurons transduced with adeno-associated virus 2.5 viral vector eGFP-tagged scrambled or CDK5 shRNA-miR during 12 days. Protection was dependent on a concomitant increase in p35 and was reversed using p35 RNAi, which affected the down-stream Rho GTPase activity. Furthermore, p35 over-expression and constitutively active Rac1 mimicked CDK5 silencing-induced neuroprotection. In addition, 3xTg-Alzheimer's disease mice (24 months old) were injected in the hippocampus with scrambled or CDK5 shRNA-miR, and spatial learning and memory were performed 3 weeks post-injection using 'Morris' water maze test. Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi.
authors: Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, Faculty of Medicine, SIU, Calle 70 N°. 52-21, University of Antioquia UdeA, Medellín, Colombia.
authors: Rafael Andres
authors: RA
authors: Posada-Duque
authors: Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, Faculty of Medicine, SIU, Calle 70 N°. 52-21, University of Antioquia UdeA, Medellín, Colombia.
authors: Alejandro
authors: A
authors: López-Tobón
authors: Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, Faculty of Medicine, SIU, Calle 70 N°. 52-21, University of Antioquia UdeA, Medellín, Colombia.
authors: Diego
authors: D
authors: Piedrahita
authors: Department of Biology, Faculty of Sciences, Laboratory of Cell and Neuronal Dynamics, Universidad de Chile, Ñuñoa, Santiago, Chile.
authors: Christian
authors: http://orcid.org/0000-0003-0335-1482
authors: C
authors: González-Billault
authors: Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, Faculty of Medicine, SIU, Calle 70 N°. 52-21, University of Antioquia UdeA, Medellín, Colombia.
authors: Gloria Patricia
authors: GP
authors: Cardona-Gomez
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D015153:Blotting, Western; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D014161:Transduction, Genetic; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D034741:RNA, Small Interfering; C484602:Rac1 protein, mouse; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5; D020830:rac1 GTP-Binding Protein
keywords: CDK5; RNAi; Rho GTPases; neuroprotection; p35