抗 tau 蛋白免疫疗法对脑型疟疾实验模型中反应性小胶质细胞增生、脑内皮病和认知功能的影响,Journal of Neurochemistry

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抗 tau 蛋白免疫疗法对脑型疟疾实验模型中反应性小胶质细胞增生、脑内皮病和认知功能的影响
Journal of Neurochemistry ( IF 4.7 ) Pub Date : 2023-10-09 , DOI: 10.1111/jnc.15972
Oscar B Akide Ndunge ₁ , Henry J Shikani ₂ , Minxian Dai ₂ , Brandi D Freeman ₂ , Mahalia S Desruisseaux _{1,

2}

Affiliation

脑型疟疾（CM）是一种潜在致命性脑病，主要由恶性疟原虫感染引起，会导致长期不良的神经精神后遗症。神经细胞损伤导致 CM 中观察到的神经功能缺损。tau 蛋白是一种轴突蛋白，在病理学上与神经退行性疾病中神经原纤维病变的形成相关，tau 蛋白的异常调节与炎症和脑微血管损害有关，并已在人类和实验性 CM (ECM) 中得到报道。据报道，在神经退行性疾病实验模型中使用病理性 tau 单克隆抗体 (PHF-1 mAB) 进行免疫治疗可减轻认知能力下降。我们研究了 PHF-1 mAB 免疫疗法是否可以预防 ECM 期间的脑内皮病、神经细胞损伤和神经炎症。使用感染伯氏疟原虫ANKA (PbA)（导致 ECM）、伯氏疟原虫NK65 (PbN)（导致严重疟疾但不感染 ECM）或未感染小鼠 (Un) 的 C57BL/6 小鼠，我们证明与 PbN 感染相比，或未感染的小鼠中，PbA 感染导致感染后 6 天出现显着的记忆障碍，这与小鼠Ser ²⁰² /Thr ²⁰⁵ (pSer ²⁰² /Thr ²⁰⁵ ) 和 Ser ^396–404 (pSer ^396–404 )的异常 tau 磷酸化有关大脑。ECM 还导致微血管充血和神经胶质细胞激活中炎症标志物的表达显着升高。PHF-1 mAB 治疗可预防 PbA 诱导的认知障碍，并显着减少 ECM 小鼠的血管充血、神经炎症和神经细胞激活。这些发现表明，tau 蛋白的异常调节会导致脑血管病变，并且在 CM 期间神经细胞损伤的发病机制中至关重要。Tau 靶向疗法可以改善疾病期间发生的神经细胞损伤和随后发生的神经认知障碍。

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Effects of anti-tau immunotherapy on reactive microgliosis, cerebral endotheliopathy, and cognitive function in an experimental model of cerebral malaria

Cerebral malaria (CM), a potentially fatal encephalopathy caused primarily by infection with Plasmodium falciparum, results in long-term adverse neuro-psychiatric sequelae. Neural cell injury contributes to the neurological deficits observed in CM. Abnormal regulation of tau, an axonal protein pathologically associated with the formation of neurofibrillary lesions in neurodegenerative diseases, has been linked to inflammation and cerebral microvascular compromise and has been reported in human and experimental CM (ECM). Immunotherapy with a monoclonal antibody to pathological tau (PHF-1 mAB) in experimental models of neurodegenerative diseases has been reported to mitigate cognitive decline. We investigated whether immunotherapy with PHF-1 mAB prevented cerebral endotheliopathy, neural cell injury, and neuroinflammation during ECM. Using C57BL/6 mice infected with either Plasmodium berghei ANKA (PbA), which causes ECM, Plasmodium berghei NK65 (PbN), which causes severe malaria, but not ECM, or uninfected mice (Un), we demonstrated that when compared to PbN infection or uninfected mice, PbA infection resulted in significant memory impairment at 6 days post-infection, in association with abnormal tau phosphorylation at Ser²⁰²/Thr²⁰⁵ (pSer²⁰²/Thr²⁰⁵) and Ser^396–404 (pSer^396–404) in mouse brains. ECM also resulted in significantly higher expression of inflammatory markers, in microvascular congestion, and glial cell activation. Treatment with PHF-1 mAB prevented PbA-induced cognitive impairment and was associated with significantly less vascular congestion, neuroinflammation, and neural cell activation in mice with ECM. These findings suggest that abnormal regulation of tau protein contributes to cerebral vasculopathy and is critical in the pathogenesis of neural cell injury during CM. Tau-targeted therapies may ameliorate the neural cell damage and subsequent neurocognitive impairment that occur during disease.

更新日期：2023-10-09

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