p35 and Rac1 underlie the neuroprotection and cognitive improvement induced by CDK5 silencing
Author
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Posada Duque, Rafael
Author
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López Tobon, Alejandro
Author
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Piedrahita, Diego
Author
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González Billault, Christian
Author
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Cardona Gómez, Gloria
Admission date
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2015-10-01T20:34:23Z
Available date
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2015-10-01T20:34:23Z
Publication date
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2015
Cita de ítem
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Journal of Neurochemistry 2015 | 134 | 354–370
en_US
Identifier
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DOI: 10.1111/jnc.13127
Identifier
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https://repositorio.uchile.cl/handle/2250/134049
General note
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Artículo de publicación ISI
en_US
Abstract
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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 12days. 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 (24months old) were injected in the hippocampus with scrambled or CDK5 shRNA-miR, and spatial learning and memory were performed 3weeks 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.