Laboratory of Biochemistry, School of Pharmacy, Nihon University, Narashinodai, Funabashi, Chiba 274-8555, Japan.
Laboratory of Alzheimer's Disease, Department of Life Science, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, 171-8588 Tokyo, Japan.
Biochim Biophys Acta Gen Subj. 2022 Jul;1866(7):130135. doi: 10.1016/j.bbagen.2022.130135. Epub 2022 Mar 28.
In 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.
Primary hippocampal neurons were treated with glutamate and examined by in situ hybridization, immunocytochemistry and Western blotting.
The 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.
Our 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.
Hyperphosphorylated 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.
在阿尔茨海默病（AD）中，脑神经元的树突干区中异常磷酸化的 tau 导致突触丧失，从而导致神经元死亡。尽管 tau 在树突中出现过度磷酸化的机制尚不清楚，但我们之前曾报道过，tau mRNA 和 GSK3β mRNA 在谷氨酸刺激下的局部翻译分别触发 tau 蛋白的增加和重新激活的预存 GSK3β 的放大循环的启动。在这项研究中，我们研究了负责树突中另一种主要 tau 激酶 CDK5 的神经兴奋依赖性激活的机制。
用谷氨酸处理原代海马神经元，并通过原位杂交、免疫细胞化学和 Western blot 进行检测。
发现 CDK5 和其神经特异性激活剂 p35 的 mRNA 均在树突中持续分布。谷氨酸处理诱导这些蛋白质的局部树突翻译以及 p35 向 p25 的转化，形成超激活的 CDK5/p25 复合物。在存在钙蛋白酶抑制剂或 NMDA 受体拮抗剂的情况下，这种由 CDK5 引起的神经兴奋依赖性 tau 磷酸化受到抑制。
我们的结果表明，除了树突 tau 的增加和预存 GSK3β 的重新激活外，NMDA 受体介导的神经兴奋还通过翻译树突分布的 mRNA 引起 CDK5 的增加和超激活。
具有 AD 表位的过度磷酸化 tau 是通过谷氨酸刺激下树突分布的 mRNA 的翻译活性在树突中局部产生的。因此，tau 过度磷酸化可能在突触转导中发挥关键作用。
