Effect of Chronic Neuroinflammation on Mouse Cognition

描述(申请人提供)：慢性神经炎是阿尔茨海默病(AD)的一个显著特征，被认为是导致最终表现为认知功能障碍的分子级联反应的原因。虽然神经胶质细胞的激活受到神经元斑块和缠结的影响，但它在老年大脑中的存在，独立于AD样神经病理，表明慢性神经炎症可能是老年性痴呆的初始组成部分和因素。此外，流行病学研究表明，在临床症状出现之前开始非类固醇抗炎药(NSAID)治疗可能有效地延缓AD高危人群认知障碍的发生。据信，推动这一神经炎症过程的一个关键因素是白介素1β，这是一种促炎细胞因子，在AD脑和其他神经退行性疾病中上调。我们发现，小鼠脑内注射IL-1β可诱导强烈的胶质反应和环氧合酶-2(COX-2)的表达，COX-2是一种负责前列腺素合成的同工酶，也是非甾体抗炎药的靶标。此外，我们还发现了慢性脑室内(I.C.V.)后持续的炎症反应。输注IL-1β。尽管已经在慢性神经炎的大鼠模型和AD的转基因小鼠神经病理学模型中进行了大量研究，但关于胶质细胞激活时间延长和脑内IL-1β浓度升高对成年小鼠行为的影响的数据很少。此外，针对持续的促炎刺激的具体性别反应的问题尚未得到解决。为了调查慢性神经炎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，我们将确立慢性I.C.V的行为后果。IL-1β输注对空间和非空间记忆的影响。雄性和雌性小鼠将被用来确定IL-1β诱导的记忆力缺陷的潜在性别差异。在第二个目标中，将对行为测试动物的神经组织进行胶质细胞激活、环氧合酶表达和胆碱能活动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联系起来。这些结果将有助于今后利用非甾体抗炎药预防/治疗炎症性记忆障碍的研究。总而言之，这些研究将描述一种小鼠模型，该模型将阐明慢性神经炎在衰老和AD相关的病理生物学和认知能力下降中的作用。

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.