Project 3

项目3

• 批准号: 10271799
• 负责人: James M. Hyman
• 金额: $ 23.85万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271799
• 关键词: APP-PS1; Acute; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Amyloidosis; Animal Model; Animals; Anterior; Appearance; Area; Behavior; Behavioral; Biological Markers; Brain; Brain region; Centers of Research Excellence; Chronic; Clinic; Cognitive; Cognitive deficits; Communication; Data; Deposition; Development; Disease Progression; Dose; Electrophysiology (science); Environment; Environmental Exposure; Exposure to; Future; Genetic; Hippocampus (Brain); Human; Immune response; Impairment; Inflammation; Inflammatory; Injections; Ion Channel; Link; Measures; Memory; Memory Loss; Memory impairment; Microglia; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nevada; Pathologic; Pathology; Pattern; Phase; Play; Poly I-C; Process; Production; Property; Protocols documentation; Reporting; Research; Retrieval; Role; Schedule; Senile Plaques; Site; Structure; Synapses; System; Tauopathies; Techniques; Time; Transgenic Animals; Transgenic Mice; Transgenic Model; Transgenic Organisms; Universities; Work; abeta deposition; activity marker; behavioral impairment; brain health; cingulate cortex; cognitive process; diagnostic biomarker; experimental study; immune activation; information processing; memory consolidation; memory encoding; memory process; memory recall; mouse model; network dysfunction; neural network; neurofibrillary tangle formation; neuroinflammation; neuron loss; novel; potential biomarker; relating to nervous system; response; targeted biomarker; tau Proteins; therapeutic target; translational neuroscience

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.

摘要/摘要 项目R-3 炎症在小鼠（Hyman博士）中与广告相关网络功能障碍中的作用 阿尔茨海默氏病（AD）是一种神经退行性疾病，其特征是记忆的逐渐丧失 功能。大量研究集中在AD，淀粉样蛋白β（Aβ）斑块的病理标志上 沉积，tau高磷酸化，神经原纤维缠结形成以及进行性丧失神经元和 突触。最近，研究表明，免疫激活，以神经炎症的形式和 相关的小胶质细胞激活可能有助于经典AD病理的发展，但角色中性 在AD患者中观察到的记忆障碍中的炎症起作用尚不清楚。记忆形成和检索 是大脑结构网络的产物，包括海马（HC）和前部 扣带皮质（ACC）。使用发展AD病理的转基因动物模型（Aβ沉积或TAU） 高磷酸化）揭示了质量发展之前的HC的电活动改变 淀粉样变性或tauopathy。这种更改的网络活动可能解释了记忆缺陷的外观 在广告进展的早期。但是，所有不同的转基因模型均显示出严重的神经炎症，但是 网络功能障碍是由于免疫反应引起的，或者经典的AD病理仍然未知。 调查神经炎症对内存链接网络活动的影响可以帮助确定未来 治疗靶标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。我们将检查神经炎症是否影响记忆处理的不同阶段（编码， 合并，检索）以及效果是否本地化与HC或ACC或是否改变了相互作用 在这些区域之间。我们计划将我们的电生理发现与神经炎症的标记相关联 更好地了解这些因素如何在改变网络活动中共同起作用。接下来，我们将检查是否 神经炎症的增加加剧了在早期病理Aβ和 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，则这些 结果支持我们的整体假设，即NI本身正在损害内存网络活动。这些数据将提供 有价值的信息，用于通过AD和AD转基因中出现记忆障碍的机制 动物模型。