{"title":"Polycyclitol Derivatives Restore Long- Term Memory Via cdk5/p25 Activation of Tau Signaling in Experimental Cerebral Malaria","authors":"Praveen Kumar Simhadri, Showkat Rashid, Shailaja Karri, Bilal A. Bhat, Goverdhan Mehta, Phanithi Prakash Babu","doi":"10.1007/s11064-025-04495-8","DOIUrl":null,"url":null,"abstract":"<div><p>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, <b>SR4-01</b> to <b>SR4-04</b>, 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, <b>SR4-02</b> and <b>SR4-04</b> demonstrated significant improvements in learning and memory compared to both artemether monotherapy and the <b>SR4-01</b> and <b>SR4-03</b> groups. Immunohistochemical analysis of the hippocampus and cortex showed reduced phospho-tau (Ser396) expression in the <b>SR4-02</b> and <b>SR4-04</b> 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 <b>SR4-04</b> treated group. Collectively, our findings suggest that <b>SR4-02</b> and <b>SR4-04</b> hold promise as adjunctive therapies for reducing tau pathology and restoring cognitive function in cerebral malaria-associated neurodegeneration.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 4","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurochemical Research","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s11064-025-04495-8","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
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.