多环醇衍生物通过cdk5/p25激活Tau信号通路在实验性脑疟疾中恢复长期记忆。

IF 3.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Praveen Kumar Simhadri, Showkat Rashid, Shailaja Karri, Bilal A. Bhat, Goverdhan Mehta, Phanithi Prakash Babu
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引用次数: 0

摘要

细胞周期蛋白依赖性激酶5 (Cdk5)是tau蛋白激酶II (TPKII)的纯化形式,通过其辅因子p25的激活介导tau异常过度磷酸化。由此产生的Cdk5-p25复合物促进促炎细胞因子IL-1β的产生,促进小胶质细胞标志物Iba-1的表达升高,Iba-1是牛头病变驱动的神经退行性疾病的一个既定特征。tau蛋白Ser396/404位点的过度磷酸化会破坏微管稳定性,导致神经元功能障碍、突触丧失和认知缺陷。值得注意的是,在撒哈拉以南非洲,约有25%的脑疟疾存活儿童出现认知障碍,这凸显了对神经保护疗法的迫切需要。在这项研究中,我们采用了一个实验性脑疟疾模型来评估四种多环衍生物SR4-01至SR4-04作为蒿甲醚的辅助剂的治疗潜力。我们评估了它们在减弱cdk5 -p25介导的tau蛋白Ser396位点过度磷酸化方面的功效,目的是恢复神经元结构和认知功能。行为评估包括长期记忆的巴恩斯迷宫,短期记忆的t型迷宫,以及基于新颖性的识别任务。在治疗组中,与蒿甲醚单药治疗组和SR4-01和SR4-03组相比,SR4-02和SR4-04在学习和记忆方面表现出显著的改善。海马和皮层的免疫组织化学分析显示,SR4-02和SR4-04组的phospho-tau (Ser396)表达降低。高尔基-考克斯染色进一步显示海马CA1和CA3亚区以及皮质的神经元树突化增强。Western blot分析证实SR4-04处理组cdk5 -p25介导的tau磷酸化降低。总之,我们的研究结果表明,SR4-02和SR4-04有望作为减少脑疟疾相关神经变性的tau病理和恢复认知功能的辅助疗法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Polycyclitol Derivatives Restore Long- Term Memory Via cdk5/p25 Activation of Tau Signaling in Experimental Cerebral Malaria

Polycyclitol Derivatives Restore Long- Term Memory Via cdk5/p25 Activation of Tau Signaling in Experimental Cerebral Malaria

Cyclin-dependent kinase 5 (Cdk5), a purified form of tau protein kinase II (TPKII), mediates abnormal tau hyperphosphorylation through activation by its cofactor p25. The resulting Cdk5-p25 complex promotes the production of the pro-inflammatory cytokine IL-1β, contributing to elevated expression of the microglial marker Iba-1, an established feature of tauopathy-driven neurodegenerative diseases. Hyperphosphorylation of tau at Ser396/404 disrupts microtubule stability, leading to neuronal dysfunction, synaptic loss, and cognitive deficits. Notably, approximately 25% of children surviving cerebral malaria in Sub-Saharan Africa experience cognitive impairments, underscoring the urgent need for neuroprotective therapies. In this study, we employed an experimental cerebral malaria model to assess the therapeutic potential of four polycyclic derivatives, SR4-01 to SR4-04, as adjuncts to artemether. We evaluated their efficacy in attenuating Cdk5-p25-mediated tau hyperphosphorylation at Ser396, with the goal of restoring neuronal architecture and cognitive function. Behavioral assessments included the Barnes maze for long-term memory, T-maze for short-term memory, and a novelty-based recognition task. Among the treatment groups, SR4-02 and SR4-04 demonstrated significant improvements in learning and memory compared to both artemether monotherapy and the SR4-01 and SR4-03 groups. Immunohistochemical analysis of the hippocampus and cortex showed reduced phospho-tau (Ser396) expression in the SR4-02 and SR4-04 groups. Golgi-Cox staining further revealed enhanced neuronal arborization in the CA1 and CA3 subregions of the hippocampus and in the cortex. Western blot analysis confirmed reduced Cdk5-p25-mediated tau phosphorylation in the SR4-04 treated group. Collectively, our findings suggest that SR4-02 and SR4-04 hold promise as adjunctive therapies for reducing tau pathology and restoring cognitive function in cerebral malaria-associated neurodegeneration.

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来源期刊
Neurochemical Research
Neurochemical Research 医学-神经科学
CiteScore
7.70
自引率
2.30%
发文量
320
审稿时长
6 months
期刊介绍: Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.
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