Mechanisms of stress-induced neurovascular damage promoting immune infiltration and depression-like behaviors

摘要： 阿尔茨海默病(AD)是一种以抗体积聚和过度磷酸化为特征的衰弱状态 被认为会导致神经退化和认知能力下降的tau蛋白。据推测，Ab. 积聚和紧张症可能会导致组成血脑屏障(BBB)的血管受损， 据估计，这导致了全世界约50%的痴呆症，包括阿尔茨海默病。这样的血脑屏障损害被认为是 通过增加脑组织通透性和外周免疫渗入导致疾病发病机制。动物 AD相关病理模型，依赖于已建立的基因突变的过度表达或敲入， 已经证实Aβ和tau的积累确实会导致血管异常和血液- 脑屏障(BBB)破坏(图1)，这与包括认知在内的行为症状有关 功能障碍。除了认知能力下降，许多AD患者还经历了严重的神经精神障碍 抑郁和焦虑等症状。而并发神经精神症状的机制与 AD并不为人所知，我们已经表明，慢性应激--人类AD的已知危险因素--实际上可以 损坏BBB。在父母R01MH104559的领导下，我的实验室一直在调查促炎症 细胞因子，如白介素6(IL-6)或免疫细胞本身，可能更容易扩散到脑部 因血管损伤而应激的小鼠。我们发现，压力降低了紧密连接的表达 蛋白claudin 5(CLDN5)，并导致内皮屏障的破坏，使更多的IL-6直接进入 进入大脑奖励区域，如伏隔核(NAC)，以损害社会行为和对自然的反应 奖励[15]。有趣的是，AD相关病理的小鼠遗传模型证实，它们确实比 对压力的行为影响敏感，并表现出与年龄相关的血脑屏障退行性变，这导致 渗透性增加。在本补充资料中，我们将研究慢性社会压力对血脑屏障完整性的影响。 以及阿尔茨海默病相关病理的成熟小鼠模型中的应激诱导行为。

Abstract: Alzheimer’s Disease (AD) is a debilitating conditioned marked by accumulation of Ab and hyperphosphorylation of tau proteins thought to lead to neurodegeneration and cognitive decline. It has been hypothesized that Ab accumulation and tauopathy might result in damage to blood vessels that make up the blood brain barrier (BBB), which is estimated to contribute to ~50% of all dementias worldwide, including AD. Such BBB damage is thought to result in disease pathogenesis by increasing brain permeability and peripheral immune infiltration. Animal models of AD-related pathology, which rely on the overexpression or knock-in of established genetic mutations, have confirmed that the accumulation of Aβ and tau does indeed result in blood vessel abnormalities and blood- brain barrier (BBB) breakdown (Fig 1), which is associated with behavioral symptoms including cognitive dysfunction. In addition to cognitive decline, many AD patients also experience severe neuropsychiatric symptoms such as depression and anxiety. While the mechanisms of comorbid neuropsychiatric symptoms with AD are not well known, we have shown that chronic stress—a known risk factor for AD in humans—can in fact damage the BBB. Under the parent R01MH104559, my lab has been investigating whether pro-inflammatory cytokines such as interleukin 6 (IL-6) or immune cells themselves may diffuse more readily into the brain of stressed mice due to vascular damage. We have found that stress reduces expression of the tight junction protein claudin 5 (CLDN5) and leads to breakdown of the endothelial barrier allowing greater entry of IL-6 directly into brain reward regions like the nucleus accumbens (NAc) to impair social behavior and responses to natural rewards [15]. Interestingly, genetic mouse models of AD-related pathology confirm that they are indeed more sensitive to the behavioral effects of stress and exhibit age-related degeneration of the BBB, which leads to increased permeability. In this supplement we will examine the effects of chronic social stress on BBB integrity and stress-induced behaviors in well-established mouse models of AD-related pathology.