Dendritic distribution of CDK5 mRNA and p35 mRNA, and a glutamate-responsive increase of CDK5/p25 complex contribute to tau hyperphosphorylation
Dendritic distribution of CDK5 mRNA and p35 mRNA, and a glutamate-responsive increase of CDK5/p25 complex contribute to tau hyperphosphorylation
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DOI：
10.1016/j.bbagen.2022.130135
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发表时间：
2022-04-01
影响因子：
3
通讯作者：
Kobayashi，Shunsuke
中科院分区：
文献类型：
--
作者：
Tanaka，Toru;Ohashi，Sachiyo;Kobayashi，Shunsuke
研究背景阿尔茨海默病（Alzheimer's disease，AD）患者脑神经元体树突区tau蛋白磷酸化异常，导致突触丧失，最终导致神经元死亡。尽管过度磷酸化tau蛋白在树突中出现的机制尚不清楚，但我们以前曾报道过，tau mRNA和GSK 3 β mRNA在对谷氨酸能刺激的反应中的局部翻译分别触发了tau蛋白的增加和重新激活的预先存在的GSK 3 β扩增的循环的启动。在这项研究中，我们调查的机制负责神经兴奋依赖性激活的另一个主要的tau激酶，CDK 5，dendrites.MethodsPrimary海马神经元用谷氨酸处理，并通过原位杂交，免疫细胞化学和Western blotting.ResultsThe mRNA的CDK 5和它的神经特异性激活剂，p35，被发现是组成性分布在树突。谷氨酸处理诱导这些蛋白质的立即局部树突状翻译以及p35转化为p25，其形成超活化的CDK 5/p25复合物。在钙蛋白酶抑制剂或NMDA受体拮抗剂的存在下，CDK 5抑制了这种神经兴奋依赖性tau蛋白磷酸化。CDK 5增加和过度活化是由NMDA受体上树突分布mRNA的翻译引起的，一般意义具有AD表位的过度磷酸化的tau蛋白通过树突分布的mRNA的翻译激活在树突中局部产生，以响应神经元能刺激。因此，tau蛋白过度磷酸化可能在突触转导中起着至关重要的作用。
BackgroundIn Alzheimer's disease (AD), abnormally phosphorylated tau in the somatodendrite compartment of brain neurons causes synaptic loss, resulting in neuron death. Although the mechanism by which hyperphosphorylated tau appears in dendrites remains unclear, we have previously reported that local translation of tau mRNA and GSK3β mRNA in response to glutamatergic stimulation triggers an increase of tau protein and initiation of a cycle for amplification of reactivated preexisting GSK3β, respectively. In this study, we investigated the mechanism responsible for neural excitation-dependent activation of another major tau kinase, CDK5, within dendrites.MethodsPrimary hippocampal neurons were treated with glutamate and examined by in situ hybridization, immunocytochemistry and Western blotting.ResultsThe mRNAs for both CDK5 and its neural-specific activator, p35, were found to be constitutively distributed in dendrites. Glutamate treatment induced immediate local dendritic translation of these proteins as well as conversion of p35 to p25, which forms the hyper-activated CDK5/p25 complex. This neural excitation-dependent tau phosphorylation by CDK5 was suppressed in the presence of a calpain inhibitor or a NMDA receptor antagonist.ConclusionOur results indicate that in addition to an increase of dendritic tau and reactivation of preexisting GSK3β, increase and hyper-activation of CDK5 are evoked by translation of dendrite-distributed mRNAs upon NMDA receptor-mediated neural excitation.General significanceHyperphosphorylated tau with AD epitopes is locally produced in dendrites via translational activation of dendrite-distributed mRNAs in response to glutamatergic stimulation. Therefore, tau hyperphosphorylation may play a crucial role in synaptic transduction.