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型干预措施淀粉样蛋白的细胞外沉积 ¿大脑中的蛋白质 (A¿) 是阿尔茨海默病 (AD) 和相关疾病的一个显着病理特征。脑血管系统中的沉积，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，它们是由 A¿ 内的突变引起的。 A的肽序列PP 基因。这些突变包括荷兰型 (E22Q) 和爱荷华型 (D23N) 突变，这些突变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，这些突变与脑微血管 A¿淀粉样蛋白沉积在促进 CAA 患者的神经炎症和痴呆中的作用 脑微血管而非实质淀粉样蛋白沉积通常与患有 AD 和 CAA 的个体的痴呆相关。 ¿ -大脑中的蛋白质前体（A¿PP），命名为Tg-SwDI，可形成早发性和广泛的纤维状脑微血管A¿我们实验室最近的工作更强有力地证明，Tg-SwDI 小鼠表现出与脑微血管淀粉样蛋白沉积相关的强烈神经炎症。此外，Tg-SwDI 小鼠表现出明显的行为表现缺陷。根据这些发现，构成该提议基础的总体假设是脑微血管原纤维 A¿在没有纤维斑块淀粉样蛋白的情况下，沉积会促进神经炎症本提案的目的是测试一种有效的抗炎化合物 COG133 的功效，COG133 是载脂蛋白 E 的一种新型肽片段，其调节微血管淀粉样蛋白的能力。这些独特的 Tg-SwDI 小鼠的神经炎症和行为表现的第一阶段研究的完成将为新的药物治疗可能减少脑微血管的原理提供证据。最终，如果成功，这种治疗方案将成为治疗阿尔茨海默病中淀粉样蛋白沉积相关神经炎症的一种新颖且有效的治疗方法。淀粉样蛋白被称为脑淀粉样血管病或 CAA，在超过 97% 的尸检确诊病例中发现。 CAA 还与神经炎症细胞的强烈激活和白细胞介素 6 (IL-6) 等炎症细胞因子的释放有关，COG133 是一种源自载脂蛋白的新型抗炎肽。 E，可以降低整个动物大脑中的 IL-6 水平 我们现在建议测试 COG133 是否可以减少表现出显着 CAA 和的 Tg-SwDI 小鼠大脑中发现的炎症。如果 COG133 可以减少大脑炎症，那么也可能改善这些动物的行为表现。