NEURON/GLIA COMMUNICATION RELEVANCE FOR AD

描述：（申请人摘要）两条证据 表明炎症机制可能在炎症反应中起着关键作用。 阿尔茨海默病（AD）的发病机制：1）免疫细胞化学研究 已经证明，激活的小胶质细胞与 成熟老年斑，AD的神经病理学标志之一，和 淀粉样蛋白中补体和急性时相蛋白的存在 斑块，2）回顾性流行病学研究显示， 抗炎药使用与AD之间呈负相关。这些 结果与已知的小胶质细胞对神经元的反应一致。 在执行巨噬细胞和免疫功能，如 吞噬作用和一氧化氮（NO）和超氧阴离子的分泌。 激活的小胶质细胞的增殖是否有助于和/或 对神经退行性和炎症机制的反应， 目前病情尚不清楚。最近的研究表明， 胆碱能毒蕈碱受体介导的细胞内Ca++升高 在培养的小胶质细胞中， 小胶质细胞亚型，表明小胶质细胞活化可能是 至少部分是由神经递质调节的。这些数据， 与已证实的小胶质细胞密切相关， 基底前脑胆碱能神经元，表明一个挑衅的关系， AD患者胆碱能神经传递减少与小胶质细胞 激活和/或功能障碍。本提案的总体目标是 提高我们对胆碱能神经元-小胶质细胞通讯的理解。 为此，本申请的具体目的是：1） 表征培养的小胶质细胞上的毒蕈碱受体亚型 并确定第二信使反应和功能后果 毒蕈碱受体激活的小胶质细胞，2）进一步 描述我们的初步发现，表明减少m1 受体激活的小胶质细胞分泌因子，3）测试 AD Z中m1毒蕈碱受体功能改变假说（形成 综述，参见Flynn等人，1995）可能由受体的氧化引起 13-环连位硫醇基团，以及小胶质细胞可能 通过分泌一氧化氮（NO）促进改变m1基础， 和4）比较毒蕈碱受体介导的对分离的 来自正常和AD大脑的小胶质细胞。这些研究的结果将 增强我们对假定的神经递质调节的理解， 小胶质细胞，提示m1毒蕈碱丢失的可能机制 AD中的受体反应性和 迄今为止用于治疗AD的胆碱能替代疗法， 并支持使用抗炎药治疗 治疗AD。

DESCRIPTION: (Applicant's Abstract) Two lines of evidence have suggested that inflammatory mechanisms may play a pivotal role in the pathogenesis of Alzheimer's disease (AD): 1) immunocytochemical studies have demonstrated that the close association of activated microglia with mature senile plaques, one of the neuropathological hallmarks of AD, and the presence of complement and acute phase proteins within amyloid plaques and, 2) retrospective epidemiological studies have revealed an inverse relationship between anti-inflammatory drug use and AD. These findings are consistent with the known response of microglia to neuronal insults in performing macrophage and immune functions such as phagocytosis and secretion of nitric oxide (NO) and superoxide anions. Whether the proliferation of activated microglia contributes and/or is a response to the neurodegenerative and inflammatory mechanisms in the disease is not clear at present. Recent studies demonstrating specific cholinergic muscarinic receptor-mediated increases of intracellular Ca++ in cultured microglial cells and the presence of the unique m5 receptor subtype on microglia, suggest that microglial activation may be regulated, at least in part, by neurotransmitters. These data, taken together with the demonstrated close association of microglia, with basal forebrain cholinergic neurons, suggest a provocative relationship between diminished cholinergic neurotransmission in AD and microglial activation and/or dysfunction. The overall goal of this proposal is to improve our understanding of cholinergic neuron-microglia communication. To this end, the specific aims of this application are: 1) to characterize the muscarinic receptor subtype(s) on cultured microglia and determine the second messenger responses and functional consequences of muscarinic receptor activation on microglia, 2) to further characterize our preliminary findings demonstrating diminished m1 receptor activation by microglial secreted factors, 3) to test the hypothesis that altered m1 muscarinic receptor function in AD Z(for review, see Flynn, et all, 1995) may result from oxidation of receptor i3-loop vicinal thiol groups, and the hypothesis that microglia may contribute to altered m1 foundation by secretion of nitric oxide (NO), and 4) to compare muscarinic receptor mediated-responses on isolated microglia from normal and AD brains. The results of these studies will enhance our understanding of putative neurotransmitter regulation of microglia, suggest a possible mechanism for the loss of m1 muscarinic receptor responsiveness in AD and the relative ineffectiveness of cholinergic replacement therapies used to date for the treatment of AD, and support the rationale for the use of anti-inflammatory drugs for the treatment of AD.