Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva P.O.B 653, Israel.
Anxiety and Stress Research Unit, Beer-Sheva Mental Health Center, Ministry of Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Department of Psychology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Brain Behav Immun. 2017 Aug;64:80-90. doi: 10.1016/j.bbi.2017.04.001. Epub 2017 Apr 3.
The renin-angiotensin system (RAS) is a major circulative system engaged in homeostasis modulation. Angiotensin II (Ang II) serves as its main effector hormone upon binding to its primary receptor, Ang II receptor type 1 (ATR). It is well established that an intrinsic independent brain RAS exists. Abnormal ATR activation both in the periphery and in the brain probably contributes to the development of Alzheimer's disease (AD) pathology that is characterized, among others, by brain inflammation. Moreover, treatment with drugs that block ATR (ATR blockers, ARBs) ameliorates most of the clinical risk factors leading to AD. Previously we showed that short period of intranasal treatment with telmisartan (a brain penetrating ARB) reduced brain inflammation and ameliorated amyloid burden (a component of Alzheimer's plaques) in AD transgenic mouse model. In the present study, we aimed to examine the long-term effect of intranasally administrated telmisartan on brain inflammation features including microglial activation, astrogliosis, neuronal loss and hippocampus-dependent cognition in five-familial AD mouse model (5XFAD). Five month of intranasal treatment with telmisartan significantly reduced amyloid burden in the cortex and hippocampus of 5XFAD mice as compared with the vehicle-treated 5XFAD group. Similar effects were also observed for CD11b staining, which is a marker for microglial accumulation. Telmisartan also significantly reduced astrogliosis and neuronal loss in the cortex of 5XFAD mice compared with the vehicle-treated group. Improved spatial acquisition of the 5XFAD mice following long-term intranasal administration of telmisartan was also observed. Taken together, our data suggest a significant role for AT1R blockage in mediating neuronal loss and cognitive behavior, possibly through regulation of amyloid burden and glial inflammation.
肾素-血管紧张素系统（RAS）是参与体内平衡调节的主要循环系统。血管紧张素 II（Ang II）作为其主要效应激素，与主要受体血管紧张素 II 受体 1（ATR）结合后发挥作用。现已证实存在内在独立的脑 RAS。外周和脑内的 ATR 异常激活可能导致阿尔茨海默病（AD）病理的发展，其特征是脑炎症等。此外，用阻断 ATR 的药物（ATR 阻滞剂，ARB）治疗可改善导致 AD 的大多数临床危险因素。我们之前表明，短期鼻腔内给予替米沙坦（一种穿透大脑的 ARB）可减轻 AD 转基因小鼠模型中的脑炎症和改善淀粉样蛋白负担（阿尔茨海默病斑块的组成部分）。在本研究中，我们旨在检查鼻内给予替米沙坦对五家族性 AD 小鼠模型（5XFAD）的脑炎症特征（包括小胶质细胞激活、星形胶质细胞增生、神经元丢失和海马依赖认知）的长期影响。与对照组相比，5XFAD 组经鼻腔给予替米沙坦 5 个月可显著降低皮质和海马中的淀粉样蛋白负担。替米沙坦还可显著降低 5XFAD 小鼠皮质中的小胶质细胞聚集标志物 CD11b 染色。与对照组相比，经鼻腔给予替米沙坦还可显著降低 5XFAD 小鼠皮质中的星形胶质细胞增生和神经元丢失。还观察到 5XFAD 小鼠经长期鼻腔给予替米沙坦后空间获得能力提高。综上所述，我们的数据表明 AT1R 阻断在介导神经元丢失和认知行为方面发挥重要作用，可能通过调节淀粉样蛋白负担和神经胶质炎症来实现。
