Neuroinflammation and Neurodegeneration in a Transgenic Alzheimer Rat with Vascular Disease

血管性痴呆（Vascular dementia，VaD）是由小血管病变引起的脑缺血性痴呆， 对白色物质的损害和相关的神经变性。尸检表明这种变化 导致大约三分之一的痴呆病例归因于混合病理学（MxD），具有两者的特征 阿尔茨海默病（AD）和VaD。MxD在老年退伍军人中特别普遍， 代谢综合征和心血管疾病等危险因素。然而，目前的AD临床试验 治疗经常排除患有MxD的患者。血管和AD病理学的相互作用仍然存在 这是难以捉摸的，部分原因是缺乏概括MxD病理学和病理学的动物模型。我们 该项目解决了这一障碍，建立了一种新的MxD大鼠模型，以阐明与MxD相关的机制。 AD的血管并发症。我们研究了有前途的治疗方法对预防MXD患者AD的影响。 模型，重点是淀粉样蛋白疫苗，以促进联合疗法的发展， 疫苗在MxD患者中的不良反应，如血管源性水肿和微出血。虽然 单纯AD患者中无症状，VaD对AD患者的影响尚不清楚。这项建议会 评估：a）VaD是否加重AD相关的Aβ和/或tau病理; B）外周和中枢神经系统的差异 相对于认知和/或神经退行性参数，VaD、AD和MxD中的炎症; c）是否 血浆内皮微粒区分VaD、AD和MxD;和d）已知的AD调节剂的作用 MXD的病理学该建议使用APP/PS1转基因AD大鼠模型，其发展与年龄相关的AD。 认知缺陷、Aβ/tau沉积和神经胶质增生。在目标1中，我们研究了这种FAD转基因在 自发性高血压卒中倾向（SHR-SP）大鼠，表现出与年龄相关的血管和白色物质 病理学、神经元损失和进行性认知缺陷。将该模型（SHR-FAD）与FAD模型进行了比较 阳性对照和非Tg大鼠[SHR-SP与对照品系WKY]的认知差异; 外周和中枢炎症、血管和实质Aβ和突触丢失;以及其他AD-和VaD- 相关的病理。将评估与特定疾病病理学对应的血浆和CSF生物标志物。 鉴定目的2研究促进淀粉样蛋白清除的干预措施：用抗- Aβ抗体和一种多效性Aβ结合分子姜黄素，以确定它们对血管Aβ的影响 在MxD的SHR-FAD模型中的沉积和脑血管疾病。我们假设VaD加重了 神经炎症，突触丢失和tau积累，但减少神经炎斑块，增加 脑血管淀粉样沉积外周抗A β抗体的脑渗透增加， 脑血管微粒和细胞粘附分子的血浆水平升高可能与 破坏血脑屏障。这些目标的完成可能为AD提供重要的知识 在患有VaD的患者中进行的试验。

Vascular dementia (VaD) is often caused by small vessel arteriosclerotic disease, resulting in ischemic damage to white matter and associated neurodegeneration. Autopsy studies indicate that such changes contribute to the roughly one-third of dementia cases attributed to mixed pathology (MxD), with features of both Alzheimer's disease (AD) and VaD. MxD is particularly prevalent among older Veterans, who have increased risk factors such as metabolic syndrome and cardiovascular disease. However, current clinical trials with AD therapeutics frequently exclude patients with MxD. The interactions of vascular and AD pathology remain elusive, in part due to the dearth of animal models that recapitulate MxD symptomology and pathology. Our project addresses this hurdle, establishing a novel rat model of MxD to elucidate mechanisms associated with vascular complications in AD. We examine the impact of promising therapeutics to prevent AD in the MxD model, focusing on amyloid vaccines, to facilitate the development of combination therapies that can minimize adverse effects of vaccine in MxD patients, such as vasogenic edema and microbleeds. Although asymptomatic in patients with pure AD, the impact on AD patients with VaD is unknown. This proposal will assess: a) if VaD exacerbates AD-associated Aβ and/or tau pathology; b) differences in peripheral and central inflammation in VaD, AD, and MxD relative to cognitive and/or neurodegenerative parameters; c) whether plasma endothelial microparticles differentiate VaD, AD, and MxD; and d) the effects of known modifiers of AD pathology on MxD. This proposal uses an APP/PS1 transgenic rat model of AD, which develops age-related cognitive deficits, Aβ/tau deposition, and gliosis. In Aim 1, we examine the impact of this FAD transgene in spontaneously hypertensive stroke-prone (SHR-SP) rats, which exhibits age-related vascular and white matter pathology, neuron loss and progressive cognitive deficits. This MxD model (SHR-FAD) is compared with FAD positive controls and nonTg rats [SHR-SP versus the control strain WKY] for differences in cognition; peripheral and central inflammation, vascular and parenchymal Aβ, and synaptic loss; and other AD- and VaD- associated pathologies. Plasma and CSF biomarkers corresponding to specific disease pathologies will be identified. Aim 2 investigates interventions that promote amyloid clearance: passive immunization with an anti- Aβ antibody and curcumin, a pleiotropic Aβ-binding molecule, to determine their effects on vascular Aβ deposition and cerebrovascular disease in the SHR-FAD model of MxD. We hypothesize that VaD exacerbates neuroinflammation, synaptic loss and tau accumulation, but reduces neuritic plaques, increasing cerebrovascular amyloid deposition. Increased cerebral penetration of the peripheral anti-Aβ antibodies and increased plasma levels of cerebrovascular microparticles and cellular adhesion molecules may parallel disruption of the blood brain barrier. Completion of these aims is likely to provide knowledge important for AD trials in patients who also have VaD.