Ugalde-Triviño Lola, Tejeda Gonzalo S, Esteban-Ortega Gema M, Díaz-Guerra Margarita
Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid 28029, Spain.
Institute of Molecular, Cell and Systems Biology, College of Veterinary Medical and Life Science, University of Glasgow, Glasgow, UK.
Theranostics. 2025 Mar 21;15(10):4654-4672. doi: 10.7150/thno.111272. eCollection 2025.
Glia reactivity, neuroinflammation and excitotoxic neuronal death are central processes to ischemic stroke and neurodegenerative diseases, altogether a leading cause of death, disability, and dementia. Given the high incidence of these pathologies and the limited efficacy of current treatments, developing brain-protective therapies that target both neurons and glial cells is a priority. Truncated neurotrophin receptor TrkB-T1, a protein produced by these cell types, plays relevant roles in excitotoxicity and ischemia. We hypothesized that interactions mediated by isoform-specific TrkB-T1 sequences might contribute to neurotoxicity and/or reactive gliosis, thus representing potential therapeutic targets. We designed cell-penetrating peptides containing TrkB-T1 isoform-specific sequences to: 1) characterize peptide delivery into rat primary cortical cultures and mice brain cortex; 2) isolate and identify the isoform interactome in basal and excitotoxic conditions; 3) analyze peptide effects on neuroinflammation and neurotoxicity using primary cultures subjected to excitotoxicity or in a mouse model of ischemia We identify here the TrkB-T1-specific interactome, poorly described to date, and demonstrate that interference of these protein-protein interactions using brain-accessible TrkB-T1-derived peptides can reduce reactive gliosis and decrease excitotoxicity-induced damage in cellular and animal models of stroke, where treatment reduces the infarct volume in male and female mice. The crucial role of TrkB-T1 in modulating microglia and astrocyte reactivity indicates that isoform-derived peptides hold promise for the development of therapies for human stroke and other excitotoxicity-associated pathologies.
神经胶质细胞反应性、神经炎症和兴奋性毒性神经元死亡是缺血性中风和神经退行性疾病的核心过程，这些疾病共同构成了死亡、残疾和痴呆的主要原因。鉴于这些疾病的高发病率以及当前治疗方法的疗效有限，开发针对神经元和神经胶质细胞的脑保护疗法成为当务之急。截短的神经营养因子受体TrkB-T1是由这些细胞类型产生的一种蛋白质，在兴奋性毒性和缺血中发挥着重要作用。我们推测，由异构体特异性TrkB-T1序列介导的相互作用可能导致神经毒性和/或反应性神经胶质增生，从而成为潜在的治疗靶点。我们设计了包含TrkB-T1异构体特异性序列的细胞穿透肽，以：1）表征肽在大鼠原代皮质培养物和小鼠脑皮质中的递送情况；2）在基础和兴奋性毒性条件下分离并鉴定异构体相互作用组；3）使用遭受兴奋性毒性的原代培养物或在缺血小鼠模型中分析肽对神经炎症和神经毒性的影响。我们在此确定了迄今为止描述较少的TrkB-T1特异性相互作用组，并证明使用可进入大脑的TrkB-T1衍生肽干扰这些蛋白质-蛋白质相互作用，可以减少反应性神经胶质增生，并降低中风细胞和动物模型中兴奋性毒性诱导的损伤，其中治疗可减少雄性和雌性小鼠的梗死体积。TrkB-T1在调节小胶质细胞和星形胶质细胞反应性方面的关键作用表明，异构体衍生肽有望用于开发治疗人类中风和其他与兴奋性毒性相关疾病的疗法。
