p35 and Rac1 underlie the neuroprotection and cognitive improvement induced by CDK5 silencing

CDK 5 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 RNA i knock down of CDK 5 reduced the formation of neurofibrillary tangles (NFT) and prevented neuronal loss in triple transgenic Alzheimer's mice. Here, we report that CDK 5 RNA i protected against glutamate‐mediated excitotoxicity using primary hippocampal neurons transduced with adeno‐associated virus 2.5 viral vector eGFP ‐tagged scrambled or CDK 5 sh RNA ‐miR during 12 days. Protection was dependent on a concomitant increase in p35 and was reversed using p35 RNA i, which affected the down‐stream Rho GTP ase activity. Furthermore, p35 over‐expression and constitutively active Rac1 mimicked CDK 5 silencing‐induced neuroprotection. In addition, 3xTg‐Alzheimer's disease mice (24 months old) were injected in the hippocampus with scrambled or CDK 5 sh RNA ‐miR, and spatial learning and memory were performed 3 weeks post‐injection using ‘Morris’ water maze test. Our data showed that CDK 5 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 GTP ase activity and contributes to the neuroprotection induced by CDK 5 RNA i. image CDK5 plays an important role in neurotransmission in the normal function of the adult brain, and dysregulation can lead to Tau hyperphosphorylation and cognitive impairment. Our findings suggest that p35/Rac1 signaling is critical in the CDK5 shRNAmiR‐induced neuroprotection against glutamate neurotoxicity and is also correlated with the recovery of cognitive function in 3xTg‐AD mice. CDK5 shRNAmiR blocks calpain activation, and the cleavage of p35 to p25 produced by glutamate, which generates neuroprotection in a p35 up‐regulation dependent mode and its down‐stream control of Rho GTPases, such as Rac1 and RhoA.