Neuroinflammation and Neurodegeneration in a Transgenic Alzheimer Rat with Vascular Disease

血管性痴呆(VaD)通常由小血管硬化性疾病引起，导致缺血性 对脑白质的损伤和相关的神经变性。尸检研究表明，这种变化 大约三分之一的痴呆症病例归因于混合病理(MXD)，两者都有特征 阿尔茨海默病(AD)和VaD。MXD在老年退伍军人中尤其普遍，他们已经增加了 代谢综合征和心血管疾病等风险因素。然而，目前AD的临床试验 治疗学经常排除患有MXD的患者。血管和AD病理的相互作用仍然存在 难以捉摸，部分原因是缺乏概括MXD症状和病理的动物模型。我们的 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 阿尔茨海默病的血管并发症。我们研究了有希望的治疗方法对预防MXD中AD的影响 模型，重点是淀粉样蛋白疫苗，以促进联合疗法的开发，可以将 疫苗对MXD患者的不良反应，如血管源性水肿和微量出血。虽然 单纯AD患者无症状，VaD对AD患者的影响尚不清楚。这项提议将 评估：a)VaD是否加重AD相关的Aβ和/或tau病理；b)外周和中枢的差异 VAD、AD和MXD的炎症与认知和/或神经退行性参数有关；c)是否 血浆内皮微粒区分VAD、AD和MXD；以及d)已知AD修饰剂的作用 MXD的病理学。这项建议使用了APP/PS1转基因AD大鼠模型，该模型与年龄相关 认知缺陷、β/tau沉积和神经胶质细胞增多症。在目标1中，我们研究了这种FAD转基因在 自发性高血压卒中易感大鼠(SHR-SP)，表现为与年龄相关的血管和白质 病理学、神经元丢失和进行性认知缺陷。将这种MXD模型(SHR-FAD)与FAD进行了比较 阳性对照组和非Tg大鼠[SHR-SP与对照品系WKY]的认知差异； 外周和中枢性炎症，血管和实质Aβ，突触丢失；以及其他AD和VAD- 相关的病理学。与特定疾病病理相对应的血浆和脑脊液生物标记物将 已确认身份。目的2研究促进淀粉样蛋白清除的干预措施：被动免疫 β抗体和多效性A-β结合分子姜黄素对血管A-β的影响 MXD SHR-FAD模型中的沉积与脑血管疾病。我们假设VAD会加剧 神经炎症、突触丢失和tau积聚，但减少神经炎斑块，增加 脑血管淀粉样物沉积。增加外周抗Aβ抗体的大脑渗透率和 血浆脑血管微粒和细胞黏附分子水平升高可能平行 破坏血脑屏障。这些目标的完成可能会为AD提供重要的知识 对同样患有vaD的患者进行试验。

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.