Effect of Chronic Neuroinflammation on Mouse Cognition

描述（由申请人提供）：慢性神经炎症是阿尔茨海默病（AD）的显著特征，并被认为有助于最终表现为认知功能障碍的分子级联反应。虽然神经胶质活化受神经元斑块和缠结的影响，但其在老年脑中的存在，独立于AD样神经病理学，表明慢性神经炎症可能是年龄相关性痴呆的初始组成部分和因素。此外，流行病学研究表明，在出现临床症状之前开始的非甾体抗炎药（NSAID）治疗可能有效延迟AD风险人群的认知障碍发作。据信驱动这种神经炎症过程的一个关键因素是白细胞介素（IL）-1 β，一种在AD脑和其他神经退行性疾病中上调的促炎细胞因子。我们发现，小鼠脑内注射IL-1 β可诱导强烈的神经胶质反应和环氧合酶（考克斯）-2的表达增加，COX-2是一种负责前列腺素合成的酶，也是NSAID的靶点。此外，我们还发现慢性脑室内（i. c. v.）输注IL-1 β。尽管在慢性神经炎症大鼠模型和AD神经病理学转基因小鼠模型中进行了大量研究，但关于胶质细胞活化延长和IL-1 β脑浓度升高对成年小鼠行为的影响的数据很少。此外，对持续促炎刺激的性别特异性反应的问题尚未得到解决。为了研究慢性神经炎症导致小鼠认知功能障碍的假设，我们提出了两个目标。在第一个目标中，我们将建立慢性i. c. v. IL-1 β输注对空间和非空间记忆的行为后果。雄性和雌性小鼠将用于确定IL-1 β诱导的记忆缺陷的潜在性别差异。在第二个目标中，将对来自行为测试动物的神经组织进行神经胶质活化、环氧合酶表达和胆碱能活性标志物的免疫组织化学分析，以将炎症的分子指标与行为表现相关联。这些结果将有利于未来的研究，预防/治疗炎症诱导的记忆功能障碍，利用NSAIDS。这些研究将共同表征小鼠模型，该模型将阐明慢性神经炎症在与衰老和AD相关的病理生物学和认知衰退中的作用。

DESCRIPTION (provided by applicant): Chronic neuroinflammation is a prominent feature of Alzheimer's disease (AD) and is believed to contribute to the molecular cascade that ultimately manifests as cognitive dysfunction. Although glial activation is influenced by neuronal plaques and tangles, its presence in the aged brain, independent of AD-like neuropathology, suggests that chronic neuroinflammation may be an initial component of, and factor in age-related dementia. Furthermore, epidemiological studies suggest that non-steroidal anti-inflammatory drug (NSAID) treatment initiated prior to display of clinical symptoms may be effective in delaying the onset of cognitive impairments in persons at-risk for AD. One key player that is believed to drive this neuroinflammatory process is lnterleukin (IL)-1beta, a pro-inflammatory cytokine that is upregulated in AD brain and other neurodegenerative disorders. We have found that intracerebral administration of IIL-1beta in mouse brain induces a robust glial response and increased expression of cyclooxygenase (COX)-2, an isoform lot the enzyme responsible for prostaglandin synthesis and the target of NSAIDs. Also, we have found a sustaining 'inflammatory response following chronic intracerebroventricular (i.c.v.) infusion of IL-1beta. Although substantial research has been conducted in rat models of chronic neuroinflammation and transgenic mouse models of AD neuropathology, data are sparse for the effect of prolonged glial activation and elevated IL-1beta brain concentrations on adult mouse behavior. Furthermore, the issue of sex-specific responses to a sustained pro-inflammatory stimulus has yet to be addressed. To investigate the hypothesis that chronic neuroinflammation contributes to cognitive dysfunction in mice, we propose two aims. In the first aim, we will establish the behavioral consequence of chronic i.c.v. lL- 1beta infusion on spatial and non-spatial memory. Male and female mice will be used to determine potential sex-difference in IL-1beta - induced mnemonic deficits. In the second aim, immunohistochemical analysis of glial activation, cyclooxygenase expression and markers of cholinergic activity will be conducted on neural tissue from the behaviorally-tested animals to correlate molecular indices of inflammation with behavioral performance. These results will be beneficial for future studies on prevention/treatment of inflammation-induced memory dysfunction utilizing NSAIDS. Together these studies will characterize a mouse model that will elucidate the role of chronic neuroinflammation in the pathobiology and cognitive decline associated with aging and AD.