Poly(I:C) promotes neurotoxic amyloid β accumulation through reduced degradation by decreasing neprilysin protein levels in astrocytes.
Poly(I:C) promotes neurotoxic amyloid β accumulation through reduced degradation by decreasing neprilysin protein levels in astrocytes.
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Poly(I:C) 通过降低星形胶质细胞中的脑啡肽酶蛋白水平来减少降解，从而促进神经毒性淀粉样蛋白 β 的积累。
DOI：
10.1111/jnc.15716
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Sobue K.
中科院分区：
文献类型：
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作者：
Yamamoto N;Tokumon T;Obuchi A;Kono M;Saigo K;Tanida M;Ikeda-Matsuo Y;Sobue K.
与神经系统的病毒感染相关的炎症已经参与神经退行性疾病（诸如阿尔茨海默病（AD）和多发性硬化症）的发病机制。聚肌胞苷酸（poly [I：C]）是一种Toll样受体3（TLR3）激动剂，可模拟对全身性病毒感染的炎症反应。尽管越来越多的人认识到胶质细胞在AD病理学中的作用，但对它们参与AD患者脑中淀粉样蛋白β（A β）的积累和清除的了解甚少。脑啡肽酶（NEP）和胰岛素降解酶（IDE）是脑内主要的A β降解酶。本研究探讨了poly（I：C）是否通过TLR3调节星形胶质细胞中NEP和IDE蛋白水平来调节A β降解和神经毒性。为此，用poly（I：C）和TLR 3信号传导抑制剂处理原代大鼠原代星形胶质细胞培养物。蛋白质水平通过蛋白质印迹进行评估。通过乳酸脱氢酶释放测定A β对原代神经元的毒性。Poly（I：C）诱导星形胶质细胞膜和培养基中的NEP水平显着降低。在poly（I：C）处理的星形胶质细胞中，外源性A β的降解显著延迟。这种延迟显著增加了外源性A β 1 - 42的神经毒性。总之，这些结果表明，病毒感染通过降低星形胶质细胞中的NEP水平从而阻止A β降解来诱导A β神经毒性。
Inflammation associated with viral infection of the nervous system has been involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD) and multiple sclerosis. Polyinosinic:polycytidylic acid (poly[I:C]) is a Toll‐like receptor 3 (TLR3) agonist that mimics the inflammatory response to systemic viral infections. Despite growing recognition of the role of glial cells in AD pathology, their involvement in the accumulation and clearance of amyloid β (Aβ) in the brain of patients with AD is poorly understood. Neprilysin (NEP) and insulin‐degrading enzyme (IDE) are the main Aβ‐degrading enzymes in the brain. This study investigated whether poly(I:C) regulated Aβ degradation and neurotoxicity by modulating NEP and IDE protein levels through TLR3 in astrocytes. To this aim, primary rat primary astrocyte cultures were treated with poly(I:C) and inhibitors of the TLR3 signaling. Protein levels were assessed by Western blot. Aβ toxicity to primary neurons was measured by lactate dehydrogenase release. Poly(I:C) induced a significant decrease in NEP levels on the membrane of astrocytes as well as in the culture medium. The degradation of exogenous Aβ was markedly delayed in poly(I:C)‐treated astrocytes. This delay significantly increased the neurotoxicity of exogenous Aβ1‐42. Altogether, these results suggest that viral infections induce Aβ neurotoxicity by decreasing NEP levels in astrocytes and consequently preventing Aβ degradation.