Simhadri Praveen Kumar, Rashid Showkat, Karri Shailaja, Bhat Bilal A, Mehta Goverdhan, Babu Phanithi Prakash
F-23/71, Neuroscience Laboratory, Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, 500 046, India.
Natural Products & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine (IIIM), Jammu, Jammu and Kashmir, 180001, India.
Neurochem Res. 2025 Jul 26;50(4):250. doi: 10.1007/s11064-025-04495-8.
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.
细胞周期蛋白依赖性激酶5（Cdk5），一种纯化形式的tau蛋白激酶II（TPKII），通过其辅因子p25的激活介导异常的tau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，导致小胶质细胞标志物Iba-1的表达升高，这是tau蛋白病驱动的神经退行性疾病的一个既定特征。tau蛋白在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25%存活的脑型疟疾儿童存在认知障碍，这突出了对神经保护疗法的迫切需求。在本研究中，我们采用实验性脑型疟疾模型评估四种多环衍生物SR4-01至SR4-04作为蒿甲醚辅助治疗的潜力。我们评估了它们在减轻Ser396位点Cdk5-p25介导的tau过度磷酸化方面的疗效，目标是恢复神经元结构和认知功能。行为评估包括用于长期记忆的巴恩斯迷宫、用于短期记忆的T迷宫以及基于新奇性的识别任务。在各治疗组中，与蒿甲醚单一疗法以及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改善。对海马体和皮质的免疫组织化学分析显示，SR4-02和SR4-04组中磷酸化tau（Ser396）的表达降低。高尔基-考克斯染色进一步显示海马体CA1和CA3亚区以及皮质中神经元分支增多。蛋白质印迹分析证实，SR4-04治疗组中Cdk5-p25介导的tau磷酸化减少。总体而言，我们的研究结果表明，SR4-02和SR4-04有望作为辅助疗法，用于减少脑型疟疾相关神经退行性变中的tau病理并恢复认知功能。
