Project 3

总结/摘要 R-3项目 炎症在小鼠Ad相关网络功能障碍中的作用（Hyman博士） 阿尔茨海默病（AD）是一种以进行性记忆丧失为特征的神经退行性疾病 功能大量研究集中在AD的病理特征--β淀粉样蛋白（Aβ）斑块上 沉积，tau蛋白过度磷酸化，神经元缠结形成，以及神经元和 突触最近，研究表明，免疫激活，以神经炎症和 相关的小胶质细胞活化，可能有助于经典AD病理的进展，但神经系统的作用， 炎症在AD患者中观察到的记忆障碍中的作用尚不清楚。记忆的形成和提取 是大脑结构互联网络的产物，包括海马体（HC）和前额叶， 扣带皮层（ACC）。使用发生AD病理（Aβ沉积或tau蛋白）的转基因动物模型 过度磷酸化）揭示了在发生肿块之前HC中的电活动改变 淀粉样变性或tau蛋白病。这种改变的网络活动可以解释记忆缺陷的出现 早期AD进展。所有不同的转基因模型都显示出严重的神经炎症，然而，无论是 网络功能障碍是由于免疫反应或经典的AD病理学仍然未知。 研究神经炎症对记忆相关网络活动的影响可以帮助确定未来的 治疗靶点和潜在的生物标志物。 项目3将研究慢性或急性神经炎症对HC和ACC网络的影响 活动我们将研究神经炎症是否影响记忆处理的不同阶段（编码， 巩固，提取），以及影响是否局限于HC或ACC或它们是否改变相互作用 这些地区之间。我们计划将我们的电生理发现与神经炎症的标志物联系起来 以更好地了解这些因素如何共同作用，改变网络活动。接下来，我们将研究 增加的神经炎症加剧了在早期病理学Aβ中观察到的改变的网络活性， tau转基因模型。如果神经炎症导致HC和ACC的网络功能障碍增加， 结果支持了我们的总体假设，即NI本身损害了记忆网络活动。这些数据将提供 有价值的信息的机制，通过记忆障碍出现在AD和AD转基因 动物模型

SUMMARY/ABSTRACT PROJECT R-3 The Role of Inflammation in Ad-Related Network Dysfunction in Mice (Dr. Hyman) Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory function. Much research has concentrated on the pathological hallmarks of AD, amyloid-beta (Aβ) plaque deposition, tau hyperphosphorylation, neurofibrillary tangle formation, and the progressive loss neurons and synapses. Recently, studies have shown that immune activation, in the form of neuroinflammation and associated microglial activation, may contribute to progression of the classic AD pathologies, but the role neural inflammation plays in memory impairments observed in AD patients is unknown. Memory formation and retrieval are the products of interconnected networks of brain structures including the hippocampus (HC) and anterior cingulate cortex (ACC). Work with transgenic animal models that develop AD pathologies (Aβ deposition or tau hyperphosphorylation) has revealed altered electrical activity in the HC prior to the development of mass amyloidosis or tauopathy. This type of altered network activity may explain the appearance of memory deficits early in AD progression. All of the different transgenic models show severe neuroinflammation, however, whether the network dysfunction is due to the immune response or the classic AD pathologies remains unknown. Investigating the impact of neuroinflammation on memory-linked network activity can help to identify future therapeutic targets and potential biomarkers. Project 3 will investigate the effects of chronic or acute neuroinflammation on HC and ACC network activity. We will examine whether neuroinflammation affects different stages of memory processing (encoding, consolidation, retrieval) and whether the effects are localized to the HC or ACC or if they alter interactions between these areas. We plan to correlate our electrophysiological findings with markers of neuroinflammation to better understand how these factors work together in altering network activity. Next, we will examine whether increased neuroinflammation exacerbates the altered network activity observed in early stage pathology Aβ and tau transgenic models. If neuroinflammation leads to increased network dysfunction in the HC and ACC, these results support our overall hypothesis that NI itself is impairing memory network activity. These data will provide valuable information for a mechanism through which memory impairments appear in AD and AD transgenic animal models.