Novel Intervention for Amyloid-Induced Neuroinflammation

描述(由申请人提供)：针对淀粉样蛋白诱导的神经炎症的新干预方法大脑中淀粉样蛋白(A？)的细胞外沉积是阿尔茨海默病(AD)和相关疾病的显著病理特征。阿尔茨海默病也常见于脑血管内纤维沉积，这种情况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，这些形式是由A？PP基因的A？肽序列中的突变引起的。这些突变包括荷兰型(E22Q)和爱荷华型(D23N)突变，它们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到了一定的作用。在患有AD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。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/爱荷华州突变的淀粉样蛋白前体(A？PP)，命名为TG-Swdi，在没有实质性纤维斑块淀粉样蛋白的情况下，发生早发性和广泛的纤维状脑微血管A？沉积。我们实验室最近的工作表明，TG-Swdi小鼠表现出强烈的神经炎症，这与脑微血管淀粉样蛋白沉积密切相关。此外，TG-Swdi小鼠表现出明显的行为表现缺陷。根据这些发现，构成这一建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A的沉积促进了神经炎症。本提案的目的是测试一种有效的抗炎化合物COG133的有效性，它是载脂蛋白E的一种新的多肽片段，它能够调节这些独特的TG-Swdi小鼠的微血管淀粉样蛋白、神经炎症和行为表现。这些第一阶段研究的完成将提供原理证据，证明一种新的药物治疗方法可以减少脑微血管淀粉样蛋白引起的神经炎症、行为缺陷和由此导致的病理。最终，如果成功，这种治疗方案将代表着一种新的有效治疗阿尔茨海默病中与淀粉样蛋白沉积相关的神经炎症的方法。PR对淀粉样蛋白诱导的神经炎症的新型干预作用纤维淀粉样脑血管沉积称为脑淀粉样血管病，简称CAA。在所有确诊为阿尔茨海默病(AD)的尸检中，超过97%的人发现了CAA。CAA还与神经炎性细胞的强烈激活和IL-6等炎性细胞因子的释放有关。我们先前已经报道了一种来源于载脂蛋白-E的新型抗炎肽COG133，它可以降低整个动物大脑中IL-6的水平。我们现在建议测试COG133是否可以减少在TG-Swdi小鼠大脑中发现的炎症，这些炎症表现为显著的CAA和神经炎症。如果COG133可以减少脑部炎症，也可能改善这些动物的行为表现。PU

DESCRIPTION (provided by applicant): Novel Intervention for Amyloid-Induced Neuroinflammation Extracellular deposition of the amyloid ¿-protein (A¿) in brain is a prominent pathological feature of Alzheimer's disease (AD) and related disorders. Fibrillar A¿ deposition in the cerebral vasculature, a condition known as cerebral amyloid angiopathy (CAA), is also commonly found in AD. Additionally, several familial monogenic forms of CAA exist that result from mutations that reside within the A¿ peptide sequence of A¿PP gene. These include Dutch-type (E22Q) and Iowa-type (D23N) mutations which cause early and severe cerebral vascular amyloid deposition. Recent studies have implicated cerebral microvascular A¿ 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 AD and CAA. Recently, we generated novel transgenic mice that express human vasculotropic Dutch/Iowa mutant amyloid ¿-protein precursor (A¿PP) in brain, designated Tg-SwDI, that develop early-onset and extensive 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 robust 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 A¿ deposition promotes neuroinflammation in the absence of fibrillar plaque amyloid. The aim of the present proposal is to test the efficacy of a potent anti-inflammatory compound, COG133, which is a novel peptide fragment of apolipoprotein E, for its ability to modulate microvascular amyloid, neuroinflammation and behavioral performance in these unique Tg-SwDI mice. Completion of these Phase 1 studies will provide proof of principle that a novel drug treatment may reduce cerebral microvascular amyloid-induced neuroinflammation, behavioral deficits and resulting pathology. Ultimately, if successful, this therapeutic regimen would represent a novel and effective treatment for neuro-inflammation associated with amyloid deposition in Alzheimer's disease. Pr Novel Intervention for Amyloid-Induced Neuroinflammation Cerbrovascular deposits of fibrillar amyloid are known as Cerebral Amyloid Angiopathy or CAA. CAA is found in greater than 97% of all autopsy confirmed cased of Alzheimer's disease (AD). CAA is also associated with robust activation of neuroinflammatory cells and the release of inflammatory cytokines like Interleukin-6 (IL-6). We have previously reported that COG133, a novel anti-inflammatory peptide derived from apolipoprotein-E, could reduce IL-6 levels in the brains of whole animals. We now propose to test whether COG133 can reduce the inflammation found in the brains of Tg-SwDI mice that display prominent CAA and neuroinflamation. If COG133 can reduce the brain inflammation, it may also improve the behavioral performance of these animals. Pu