INFLAMMATORY MECHANISMS IN ALZHEIMERS DISEASE

描述(改编自申请者摘要)：炎症介质 已被广泛报道在阿尔茨海默病(AD)中，约有21例临床 到目前为止的研究表明，抗炎药物可能会延缓 使阿尔茨海默病的发病或减缓进展。NIA正在进行一项多中心 一场抗炎的审判。几家主要的制药和生物技术公司 公司正在寻求与AD炎症相关的策略。仍然有很多事情要做 然而，要阐明具体的机制，还需要做一些工作。此外，如何 炎症在十年或更长的病程中持续，尽管 大量证据表明，炎症消退机制在 广告，是一个几乎没有人解决的问题。在此应用程序中 我们对炎症是如何产生的提出了一个全面的假设 持续，并导致阿尔茨海默病的神经变性。这一假说存在分歧。 三个特定目标：阿尔茨海默病诱导促炎分子 病理学；促炎分子的神经毒性作用；以及 完成促炎分子和AD病理之间的循环。 在第一个具体目标中，我们将评估和演示以下机制 暴露所致的三种主要炎症类型 以教唆和神经原纤维缠绕材料(NFT)。在第二个具体例子中 目的我们将评估和论证阿司匹林的神经毒性机制。 这些Abeta/NFT介导的炎症过程。在第三个具体目标中 我们将评估和演示AD炎症的传播机制 返回以进一步刺激Abeta生产，产生潜在的 恶性循环。这些目标背后的初步数据包括 三个新发现：Abeta增加AD小胶质细胞补体的表达， 细胞因子和apoE；NFTs以抗体非依赖性激活补体 时尚；补充组件C1q提高了应用程序的内部化和 Aβ分泌增加10倍，推测是通过阻断 α-分泌酶分裂。这些新的促炎剂之间的相互作用 分子和AD病理有助于为炎症相关的治疗提供信息 工业界目前正在采取的方法，尤其是可以提供 对可能抑制AD脑部炎症的新药物的见解 保留完整的外周炎症过程(其中一些是 有益的)(例如，清除免疫复合体)。

DESCRIPTION (Adapted from Applicant's Abstract): Inflammatory mediators have been widely reported in Alzheimer's disease (AD), and some 21 clinical studies to date have suggested that anti-inflammatory drugs may delay the onset or slow the progression of AD. The NIA is conducting a multicenter trial of an anti-inflammatory. Several major pharmaceutical and biotech firms are pursuing AD inflammation-related strategies. Much still remains to be done, however, to elucidate specific mechanisms. Moreover, how inflammation is sustained over a disease course of a decade or more, despite abundant evidence that inflammation-quenching mechanisms are upregulated in AD, is a question that virtually no one has addressed. In this application we put forward an overall hypothesis for how inflammation might arise, be sustained, and cause neurodegeneration in AD. This hypothesis is divided into three specific aims: induction of pro-inflammatory molecules by AD pathology; neurotoxic actions of the pro-inflammatory molecules; and completing the loop between the pro-inflammatory molecules and AD pathology. In the first specific aim we will evaluate and demonstrate mechanisms for the induction of three major inflammatory classes as the result of exposure to Abet and neurofibrillary tangle material (NFTs). In the second specific aim we will evaluate and demonstrate mechanisms for the neurotoxicity of these Abeta/NFT-mediated inflammatory processes. In the third specific aim we will evaluate and demonstrate mechanisms by which AD inflammation feeds back to further foment Abeta production, yielding the potential for a vicious cycle. Included in the preliminary data underlying these aims are three new findings: Abeta increases AD microglial expression of complement, cytokines, and apoE; NFTs activate complement in an antibody-independent fashion; and complement component C1q increases APP internalization and Abeta secretion by as much as 10-fold, putatively by blocking alpha-secretase cleavage. These novel interactions between pro-inflammatory molecules and AD pathology can help inform inflammation-related therapeutic approaches now being pursued by industry and, in particular, may provide insights to novel agents that might inhibit AD brain inflammation while leaving intact peripheral inflammatory processes (some of which are beneficial) (e.g., immune complex clearance).