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P120-catenin is necessary for neuroprotection induced by CDK5 silencing in models of Alzheimer's disease.

ABSTRACT: Cyclin-dependent kinase 5 (CDK5) plays important roles in synaptic function. Its unregulated over-activation has been, however, associated with neurodegeneration in Alzheimer's disease. Our previous studies revealed that CDK5 silencing ameliorates tauopathy and spatial memory impairment in the 3xTgAD mouse model. However, how CDK5 targeting affects synaptic adhesion proteins, such as those involved in the cadherin/catenin system, during learning and memory processes is not completely understood. In this study, we detected reduced expression of p120 catenin (p120 ctn), N-cadherin, and ?-catenin in the brain of human Alzheimer's disease patients, in addition to a reduced PSD95 and GluN2B protein levels in a 3xTgAD mouse model. Such decrease in synaptic proteins was recovered by CDK5 silencing in mice leading to a better learning and memory performance. Additionally, CDK5 inhibition or knockout increased p120 ctn levels. Moreover, in a glutamate-induced excitotoxicity model, CDK5 silencing-induced neuroprotection depended on p120 ctn. Together, those findings suggest that p120 ctn plays an important role in the neuronal dysfunction of Alzheimer's disease models and contributes to CDK5 silencing-induced neuroprotection and improvement of memory function. p120ctn is part of the synaptic adhesion molecular complex N-cadh/p120ctn/B-ctn/PSD95, and it has a pivotal role in cell adhesion stabilization and dendritic spine modulation. Our data show that synaptic adhesion complex is affected in AD human brains and in AD models. This complex is recovered by the silencing of CDK5, preventing memory dysfunction in an AD mice model and contributing to the neuroprotection in a depend-mode of p120ctn.

SUBMITTER: Uribe-Arias A

PROVIDER: S-EPMC4980216 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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p120-catenin is necessary for neuroprotection induced by CDK5 silencing in models of Alzheimer's disease.

Uribe-Arias Alejandro A Posada-Duque Rafael Andrés RA González-Billault Christian C Villegas Andrés A Lopera Francisco F Cardona-Gómez Gloria Patricia GP

Journal of neurochemistry 20160705 4

Cyclin-dependent kinase 5 (CDK5) plays important roles in synaptic function. Its unregulated over-activation has been, however, associated with neurodegeneration in Alzheimer's disease. Our previous studies revealed that CDK5 silencing ameliorates tauopathy and spatial memory impairment in the 3xTgAD mouse model. However, how CDK5 targeting affects synaptic adhesion proteins, such as those involved in the cadherin/catenin system, during learning and memory processes is not completely understood. ...[more]

PMID: 27273428

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Project description:Background: Alzheimer's disease (AD) is characterized by amyloid beta (A?) accumulation in the brain, which triggers the activation of microglia; in turn, microglia release neuroinflammatory factors capable of damaging neurons. Thus, a therapeutic approach targeting this sustained microglia-induced inflammatory response deserves investigation. Here, we examined whether oxiracetam (ORC), a nootropic of the racetam family, can indirectly prevent A?-induced neurotoxicity by attenuating microglial activation. Methods: A?42 oligomers were used to stimulate BV2 microglial cells, and the morphological changes and phagocytic capacity of BV2 cells were evaluated using fluorescence microscopy. We used quantitative reverse transcription polymerase chain reaction to assess the inhibitory effects of ORC on A?-induced mRNA levels of interleukin-1? (IL-1?), IL-6, and tumor necrosis factor-? (TNF-?); enzyme-linked immunosorbent assay was used to examine the productions of these cytokines. We also assessed the mRNA level of inducible nitric oxide synthase and the production of nitric oxide (NO). The conditioned medium from BV2 cells was used to culture hippocampal HT22 cells to assess indirect toxicity using the MTT assay. Results: ORC prevented the A?-induced activation of BV2 cells, as reflected by reduced morphological changes and phagocytic ability. In addition, ORC downregulated the expression of A?-induced cytokines (IL-1?, IL-6, and TNF-?) and the production of NO in BV2 cells. Furthermore, ORC protected HT22 cells from indirect damage evoked by A?-treated BV2 cell-conditioned medium, but not from direct A?-induced toxicity. Conclusions: ORC suppressed the activation of BV2 cells, decreased the production of A?-induced inflammatory molecules and NO in BV2 cells, and protected HT22 cells against indirect toxicity mediated by A?-treated BV2 cell-conditioned medium. Thus, ORC may exert a protective role in AD through attenuating the damage caused by inflammation and oxidative stress.

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P120-catenin is necessary for neuroprotection induced by CDK5 silencing in models of Alzheimer's disease.

Publications

p120-catenin is necessary for neuroprotection induced by CDK5 silencing in models of Alzheimer's disease.

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