Aging Vulnerability to Inflammatory Processes

描述（由申请人提供）：阿尔茨海默病（AD）研究中的一个重要问题是确定为什么特定的大脑区域和神经系统会受到痴呆症症状进展的影响，并确定哪些机制会减缓这些过程的进展。这个建议是我之前的研究的延续，旨在了解神经炎症在阿尔茨海默病大脑退化中的作用。颞叶和前脑胆碱能神经元的退化或功能障碍与阿尔茨海默病相关的痴呆有关，我的初步研究表明，颞叶和基底前脑乙酰胆碱神经元选择性地易受慢性神经炎症的神经毒性作用的影响。目前的一系列研究将检测四种不同类型小鼠脑内慢性神经炎症的影响：1)非转基因对照小鼠，或表达2)瑞典突变淀粉样蛋白前体蛋白APP （Tg2576; K670N/M671L; Hsiao, et al., 1996）的转基因小鼠，3)突变早老素1型（PS1 line 5.1; M146L; Duff, et al., 1996）基因，或4)同时表达两种基因。这些小鼠的阿尔茨海默病样表型已经得到了很好的表征。提出的具体目标将测试炎症蛋白影响阿尔茨海默病患者大脑神经元退化的病理生理过程的总体假设。我进一步预测，慢性神经炎症引起的病理程度将在β -淀粉样蛋白和PS1突变的共同存在下加剧。在本提案，生化，病理和行为后果的慢性神经炎症产生的输注脂多糖（LPS）。脂多糖是革兰氏阴性菌细胞壁的一种成分，已被实验用于刺激内源性细胞因子和其他炎症蛋白的产生。我们在第4脑室灌注LPS的初步研究发现，最大的炎症反应包含在基底前脑、海马，特别是齿状回，以及内嗅和梨状腺皮层。提出的研究将探讨炎症过程参与细胞和分子功能障碍的初始阶段的假设，这些功能障碍可能改变细胞的脆弱性，这些变化可能反过来导致细胞死亡和认知障碍。此外，这些研究将调查这些过程的脆弱性是否与年龄相关。最后，由于导致神经元变性的级联生化过程可能涉及前列腺素的产生，因此拟议的研究还将调查是否有可能拮抗这些过程并提供神经保护。一旦完成，这项研究将大大提高我们对炎症在阿尔茨海默病大脑神经变性中的作用的理解，并将大大提高我的繁殖能力，然后使用潜在的药物治疗，这是阿尔茨海默病患者大脑神经元变性的重要步骤。

DESCRIPTION (provided by applicant): An important questions in research on Alzheimer's Disease (AD) is to define why specific brain regions and neural systems are affected with the progression of the symptoms of dementia and to determine what mechanisms will slow the progression of these processes. This proposal is a continuation of my previous studies aimed at understanding the role of neuro-inflammation in the degeneration of the AD brain. The degeneration or dysfunction of the temporal lobe and forebrain cholinergic neurons are responsible for aspects of the dementia associated with AD and my preliminary studies indicate that temporal lobe and basal forebrain acetylcholine neurons are selectively vulnerable to the neurotoxic effects of chronic neuroinflammation. The current series of studies will examine the effects of chronic neuroinflammation within the brain of four different types of mice: 1) non-transgenic control mice, or transgenic mice that express either, 2) the Swedish mutant amyloid precursor protein, APP (Tg2576; K670N/M671L; Hsiao, et al., 1996), 3) the mutant presenilin type1 (PS1 line 5.1; M146L; Duff, et al, 1996) gene or, 4) both genes simultaneously. The Alzheimer's-like phenotype present in these mice has already been well characterized. The proposed specific aims will test the overall hypothesis that inflammatory proteins influence the pathophysiological processes that underlie the degeneration of neurons in brains of people with AD. I further predict that the extent of pathology induced by the chronic neuroinflammation will be exacerbated in the combined presence of the Beta-amyloid and PS1 mutations. In the present proposal, the biochemical, pathological and behavioral consequences of chronic neuroinflammation produced by the infusion of Iipopolysaccharide (LPS). LPS is a component of the cell wall of gram-negative bacteria and has been used experimentally to stimulate the production of the endogenous cytokines and other inflammatory proteins. Our preliminary studies using LPS infusion into the 4th ventricle, found that the greatest inflammatory response was contained within the basal forebrain, hippocampus, particularly the dentate gyrus, as well as within the entorhinal and piriforin cortexes. The proposed studies will explore the hypothesis that inflammatory processes are involved in the initial stages of cellular and molecular dysfunction that may alter cellular vulnerability and that these changes may in turn lead to cell death and cognitive impairments. In addition, these studies will investigate whether there is an age-associated increase in the vulnerability to these processes. Finally, because the cascade of biochemical processes that leads to neuronal degeneration may involve the production of prostaglandins the proposed studies will also investigate whether it is possible to antagonize these processes and provide neuroprotection. Once accomplished, the research will significantly enhance our understanding of the role of inflammation in neurodegeneration in the AD brain and will greatly improve my ability to reproduce, and then manipulate with potential pharmacotherapies, important steps in the degeneration of neurons in the brain of AD patients.