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）的一个显著特征，被认为与最终表现为认知功能障碍的分子级联反应有关。尽管神经胶质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非甾体抗炎药（NSAID）治疗可能有效地延缓AD高危人群认知障碍的发生。据信，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，这是一种在AD大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，在小鼠脑内给予il -1 β可诱导强大的胶质反应，并增加环氧化酶(COX)-2的表达，COX -2是负责前列腺素合成的酶的异构体，也是非甾体抗炎药的靶标。此外，我们还发现慢性脑室内（i.c.v.）输注il -1 β后存在持续的炎症反应。尽管在慢性神经炎症的大鼠模型和AD神经病理学的转基因小鼠模型中进行了大量的研究，但关于神经胶质激活时间延长和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，性别特异性反应对持续促炎刺激的问题尚未得到解决。为了研究慢性神经炎症对小鼠认知功能障碍的影响，我们提出了两个目标。在第一个目的中，我们将建立慢性脑损伤中lL- 1 β输注对空间和非空间记忆的行为影响。雄性和雌性小鼠将被用来确定il -1 β诱导的记忆缺陷的潜在性别差异。在第二个目标中，将对行为测试动物的神经组织进行神经胶质活化、环氧化酶表达和胆碱能活性标记物的免疫组织化学分析，以将炎症分子指标与行为表现联系起来。这些结果将有助于未来使用非甾体抗炎药预防/治疗炎症性记忆功能障碍的研究。这些研究将共同描述一个小鼠模型，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.