Cerebral Microvascular Amyloid: Neuroinflammation and Cognitive Deficits

描述（由申请人提供）：脑中淀粉样蛋白（A）的细胞外沉积是阿尔茨海默病（AD）和相关疾病的突出病理特征。脑实质A区沉积可作为几乎没有周围病变的弥漫性斑块或作为与营养不良神经元和炎症相关的纤维状斑块发生。原纤维A脑血管中的淀粉样蛋白沉积，一种称为脑淀粉样血管病（CAA）的病症，也常见于阿尔茨海默病。此外，存在几种家族性单基因形式的CAA，其由存在于ASPP基因的A肽序列内的突变引起，包括荷兰型（E22 Q）和爱荷华型（D23 N），其引起早期和严重的脑血管淀粉样蛋白沉积。最近的研究表明，脑微血管AS沉积促进CAA患者的神经炎症和痴呆。在阿尔茨海默病和CAA患者中，脑微血管而非脑实质淀粉样蛋白沉积更常与痴呆相关。神经炎症仍然是治疗中枢神经系统淀粉样蛋白沉积疾病的可行靶点，特别是与脑微血管淀粉样蛋白相关的神经炎症。 最近，我们产生了新的转基因小鼠，表达人血管亲荷兰/爱荷华州突变的人淀粉样蛋白B-蛋白前体（ASPP）在大脑中，命名为Tg-SwDI，开发早发性和强大的纤维状脑微血管A？沉积在没有实质纤维斑块淀粉样蛋白。我们实验室最近的工作表明，Tg-SwDI小鼠表现出与脑微血管淀粉样蛋白沉积密切相关的神经炎症。此外，Tg-SwDI小鼠表现出明显的行为表现缺陷。根据这些发现，形成该提议的基础的总体假设是，在没有纤维斑块淀粉样蛋白的情况下，脑微血管纤维AB沉积促进神经炎症和行为缺陷。在本提案中，我们计划彻底表征微血管淀粉样蛋白和神经炎症反应，以及研究抗炎药物治疗对调节Tg-SwDI小鼠中微血管淀粉样蛋白、神经炎症和行为下降的影响，Tg-SwDI小鼠是一种新颖独特的转基因模型，仅产生微血管纤维状A？沉积。这些研究的完成应该为微血管淀粉样蛋白介导的神经炎症和痴呆提供重要的见解，这是一个未充分研究的，可能是重要的，涉及CAA的疾病方面。此外，由于CAA病理学常见于阿尔茨海默病中，因此该病理学靶点可能对这种神经退行性疾病及其相关CAA疾病的联合治疗策略具有深远的影响。

DESCRIPTION (provided by applicant): Extracellular deposition of the amyloid ¿-protein (A¿) in brain is a prominent pathological feature of Alzheimer's disease (AD) and related disorders. Cerebral parenchymal A¿ deposition can occur as diffuse plaques, with little surrounding pathology, or as fibrillar plaques associated with dystrophic neurons and inflammation. Fibrillar A¿ deposition in the cerebral vasculature, a condition known as cerebral amyloid angiopathy (CAA), is also commonly found in Alzheimer's disease. Additionally, several familial monogenic forms of CAA exist that result from mutations that reside within the A¿ peptide sequence of ASPP gene including Dutch- type (E22Q) and Iowa-type (D23N) which cause early and severe cerebral vascular amyloid deposition. Recent studies have implicated cerebral microvascular AS deposition in promoting neuroinflammation and dementia in patients with CAA. Cerebral microvascular, but not parenchymal, amyloid deposition is more often correlated with dementia in individuals afflicted with Alzheimer's disease and CAA. Neuroinflammation remains a viable target for the treatment of amyloid-depositing diseases in the central nervous system, particularly the neuroinflammation associated with cerebral microvascular amyloid. Recently, we generated novel transgenic mice that express human vasculotropic Dutch/Iowa mutant human amyloid B-protein precursor (ASPP) in brain, designated Tg-SwDI, that develop early-onset and robust fibrillar cerebral microvascular A¿ deposition in the absence of parenchymal fibrillar plaque amyloid. More recent work from our laboratory has demonstrated that Tg-SwDI mice exhibit neuroinflammation that is strongly associated with the cerebral microvascular amyloid deposition. Furthermore, Tg-SwDI mice show marked deficits in behavioral performance. In light of these findings, the overall hypothesis that forms the basis for this proposal is that cerebral microvascular fibrillar AB deposition promotes neuroinflammation and behavioral deficits in the absence of fibrillar plaque amyloid. In the present proposal, we plan to thoroughly characterize the microvascular amyloid and the neuroinflammatory response, as well as investigate the effects of anti-inflammatory drug treatment on modulating microvascular amyloid, neuroinflammation, and behavioral decline in Tg-SwDI mice, a novel and unique transgenic model that only develops microvascular fibrillar A¿ deposition. Completion of these studies should provide important insight into microvascular amyloid-mediated neuroinflammation and dementia that is an understudied and likely important, aspect of disorders that involve CAA. Additionally, since CAA pathology is commonly found in Alzheimer's disease this pathologic target may have far reaching implications in combined treatment strategies for this neurodegenerative condition and its related CAA disorders.