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

应激引起的神经血管损伤促进免疫浸润和抑郁样行为的机制

基本信息

批准号：
10121484
负责人：
SCOTT JAMES RUSSO
金额：
$ 42.38万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2020-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10121484
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid beta-Protein Anhedonia Animal Model Anxiety Area Astrocytes Award Behavior Behavioral Behavioral Symptoms Blood Blood - brain barrier anatomy Blood Vessels Brain Brain Injuries Brain region Cells Chronic Chronic stress Clinical Research Coupled Cytometry DNA Sequence Alteration Dementia Diffuse Disease Endothelial Cells Endothelium Etiology Exhibits Genetic Genotype Goals Human Immune Immune response Immune signaling Immunologics Impaired cognition Impairment Infiltration Inflammatory Inflammatory Response Interleukin-6 Knock-in Lead Measures Mediating Mental Depression Mental disorders Modeling Monitor Mus Nerve Degeneration Nucleus Accumbens Parents Pathogenesis Pathology Peripheral Permeability Play Predisposition Proteins Rewards Risk Factors Role Signal Transduction Social Behavior Social Interaction Stress Study models Surface Antigens Syndrome Tauopathies Testing Tight Junctions Transgenic Mice Tumor-infiltrating immune cells Wild Type Mouse Work abeta accumulation age related behavioral phenotyping behavioral response blood damage blood-brain barrier permeabilization brain parenchyma brain reward regions comorbidity cytokine data submission experience immune depression insight monocyte mouse model neural circuit neuropsychiatric symptom neuropsychiatry neurovascular injury overexpression preclinical study recruit response social social defeat social stress stress related disorder symptomatology tau Proteins

项目摘要

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.

抽象的：阿尔茨海默氏病（AD）是一种使AB和高磷酸化积累标记的衰弱的条件被认为会导致神经变性和认知下降的tau蛋白。已经假设AB 积累和tauopathy可能会导致构成血脑屏障（BBB）的血管损害，据估计，在包括AD在内的全球所有痴呆症中约有50％。这种BBB损害被认为是通过增加脑渗透性和外周免疫浸润而导致疾病发病机理。动物依赖于已建立的基因突变的过表达或敲门的AD相关病理模型已经证实，Aβ和TAU的积累确实确实导致血管异常和血液 - 脑屏障（BBB）故障（图1），这与行为症状有关功能障碍。除了认知能力下降外，许多AD患者还经历了严重的神经精神病学抑郁和动画等症状。而合并神经精神症状的机制与广告尚不清楚，我们已经表明，慢性压力（人类广告中已知的危险因素）实际上可以损坏BBB。在父母R01MH104559下，我的实验室一直在研究促炎性细胞因子（例如白介素6（IL-6）或免疫细胞本身）可能会更容易扩散到大脑中由于血管损伤引起的压力小鼠。我们发现应力减少了紧密连接的表达蛋白质Claudin 5（CLDN5），导致内皮屏障的崩溃，可以直接进入IL-6 进入大脑奖励区域，例如伏伏核（NAC），以损害社会行为和对自然的反应奖励[15]。有趣的是，与广告相关病理的遗传小鼠模型证实，它们确实更多对压力和表现出与年龄相关的变性的行为影响敏感，这导致渗透率提高。在这种补充中，我们将研究慢性社会压力对BBB完整性的影响以及与广告相关病理的良好小鼠模型中的压力诱导的行为。