INFLAMMATORY MECHANISMS IN ALZHEIMERS DISEASE

描述（改编自申请人的摘要）：炎症介质 已被广泛报道在阿尔茨海默病（AD），和一些21个临床 迄今为止的研究表明，抗炎药可能会延迟 或减缓AD的进展。 NIA正在进行多中心的 消炎药的试验 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。 仍有许多工作 然而，为了阐明具体的机制，还需要做些工作。 而且，如何 炎症在十年或更长的病程中持续，尽管 大量的证据表明，炎症淬灭机制上调， AD，是一个几乎没有人解决的问题。 本申请中 我们提出了一个关于炎症如何发生的总体假设， 持续，并导致AD的神经变性。 这一假设是分裂的 分为三个具体的目标：诱导促炎分子的AD 促炎分子的神经毒性作用;以及 完成促炎分子和AD病理学之间的循环。 在第一个具体目标中，我们将评估和演示以下机制： 由于暴露导致的三种主要炎症类型的诱导 Abet和神经缠结材料（NFT）。 在第二个具体 目的：我们将评估和证明神经毒性的机制， 这些Abeta/NFT介导的炎症过程。 第三个具体目标 我们将评估和证明AD炎症的机制， 回到进一步煽动Abeta生产，产生潜在的 恶性循环 这些目标所依据的初步数据包括 三项新发现：Abeta增加了AD小胶质细胞补体的表达， 细胞因子和apoE; NFT以抗体非依赖性方式激活补体 补体成分C1 q增加APP内化， Abeta分泌高达10倍，通过阻断 α-分泌酶裂解。 这些新的相互作用， 分子和AD病理学可以帮助告知炎症相关的治疗 目前工业界正在采用的方法，特别是可以提供 对可能抑制AD脑炎症的新型药物的见解， 留下完整的外周炎性过程（其中一些是 有益的）（例如，免疫复合物清除）。

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).