Novel Intervention for Amyloid-Induced Neuroinflammation

针对淀粉样蛋白引起的神经炎症的新干预措施

• 批准号: 7269009
• 负责人: MICHAEL PETER VITEK
• 金额: $ 26.34万
• 依托单位: COGNOSCI, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7269009
• 关键词: Alzheimer' s Disease; Amyloid; Amyloid deposition; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Autopsy; Behavioral; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; Cells; Cerebral Amyloid Angiopathy; Cerebrum; Condition; Dementia; Deposition; Disease; Encephalitis; Exhibits; Genes; Human; Individual; Inflammation; Inflammatory; Interleukin-6; Intervention; Iowa; Laboratories; Light; Mus; Mutation; Pathology; Patients; Peptide Fragments; Peptides; Performance; Pharmaceutical Preparations; Phase I Clinical Trials; Production; Protein Precursors; Proteins; Reporting; Senile Plaques; Testing; Therapeutic; Transgenes; Transgenic Mice; Treatment Protocols; Work; aged; amyloid induced neuroinflammation; base; capillary; cytokine; early onset; extracellular; improved; microvascular amyloid; mutant; neuroinflammation; novel; protein aminoacid sequence; therapeutic target

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

描述（由申请人提供）：淀粉样蛋白诱导的神经炎症的新干预脑中淀粉样蛋白（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。脑血管系统中的原纤维A？沉积，一种称为脑淀粉样血管病（CAA）的疾病，也常见于AD。此外，存在几种家族性单基因形式的CAA，其由位于A？PP基因的A？肽序列内的突变引起。这些包括荷兰型（E22Q）和爱荷华型（D23N）突变，它们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A？沉积促进CAA患者的神经炎症和痴呆。在患有AD和CAA的个体中，脑微血管而非脑实质淀粉样蛋白沉积更常与痴呆相关。最近，我们产生了新的转基因小鼠，表达人血管亲荷兰/爱荷华州突变淀粉样蛋白前体（A <$PP）在大脑中，指定Tg-SwDI，开发早发性和广泛的纤维状脑微血管A <$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，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A？沉积促进神经炎症。本提案的目的是测试有效的抗炎化合物COG133的功效，COG133是载脂蛋白E的新型肽片段，其调节这些独特的Tg-SwDI小鼠中的微血管淀粉样蛋白、神经炎症和行为表现的能力。这些I期研究的完成将提供一种新的药物治疗可以减少脑微血管淀粉样蛋白诱导的神经炎症、行为缺陷和由此产生的病理学的原则证据。最终，如果成功的话，这种治疗方案将代表一种新的和有效的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。淀粉样蛋白诱导的神经炎症的新干预方法纤维状淀粉样蛋白的脑血管沉积称为脑淀粉样血管病或CAA。在所有尸检证实的阿尔茨海默病（AD）病例中，CAA占97%以上。CAA还与神经炎性细胞的强烈活化和炎性细胞因子如白细胞介素-6（IL-6）的释放相关。我们以前曾报道，COG133，一种新的抗炎肽来源于载脂蛋白E，可以降低整个动物的大脑中的IL-6水平。我们现在建议测试COG133是否可以减少Tg-SwDI小鼠大脑中发现的炎症，这些小鼠表现出显著的CAA和神经炎症。如果COG133可以减轻大脑炎症，它也可能改善这些动物的行为表现。PU