Cerebral Microvascular Amyloid: Neuroinflammation and Cognitive Deficits

描述(申请人提供)：淀粉样蛋白(A)在脑细胞外沉积是阿尔茨海默病(AD)及相关疾病的显著病理特征。脑实质A？沉积可以表现为弥漫性斑块，周围几乎没有病理改变，也可以是与营养不良神经元和炎症相关的纤维斑块。阿尔茨海默氏症也常见于脑血管中的纤维沉积，这种情况被称为脑淀粉样血管病(CAA)。此外，存在几种家族性单基因形式的CAA，它们是由ASPP基因A？肽序列中的突变引起的，包括荷兰型(E22Q)和爱荷华型(D23N)，这会导致早期和严重的脑血管淀粉样蛋白沉积。最近的研究表明，脑微血管沉积在促进CAA患者的神经炎症和痴呆方面起着重要作用。在患有阿尔茨海默病和CAA的人中，大脑微血管而不是实质的淀粉样蛋白沉积更常与痴呆症相关。神经炎症仍然是治疗中枢神经系统淀粉样沉积疾病的有效靶点，特别是与脑微血管淀粉样变性相关的神经炎症。 最近，我们培育了新的转基因小鼠，在脑内表达人亲血管荷兰/爱荷华州突变的人淀粉样B蛋白前体(ASPP)，命名为TG-Swdi，在没有实质性纤维斑块淀粉样蛋白的情况下，发生早发性和强烈的纤维状脑微血管A？沉积。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，构成这一提议基础的总体假设是，在没有纤维斑块淀粉样蛋白的情况下，大脑微血管纤维AB沉积促进神经炎症和行为缺陷。在目前的提案中，我们计划彻底表征微血管淀粉样蛋白和神经炎性反应，并研究抗炎药物治疗对TG-Swdi小鼠微血管淀粉样蛋白、神经炎症和行为下降的调节作用，这是一种仅产生微血管纤维A‘沉积的新型和独特的转基因模型。这些研究的完成将为微血管淀粉样蛋白介导的神经炎症和痴呆提供重要的洞察力，这是涉及CAA的疾病中一个未被充分研究且可能很重要的方面。此外，由于CAA病理常见于阿尔茨海默病，这一病理目标可能对这种神经退行性疾病及其相关的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.