Project 3

项目3

• 批准号: 10688060
• 负责人: James M. Hyman
• 金额: $ 17.14万
• 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/10688060
• 关键词: APP-PS1; Acute; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; 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; Genes; Genetic; Hippocampus; Human; Immune response; Impairment; Inflammation; Inflammatory; Injections; Ion Channel; Learning; Link; Measures; Memory; Memory Loss; Memory impairment; Microglia; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; 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; beta amyloid pathology; brain health; cingulate cortex; cognitive process; diagnostic biomarker; experimental study; glial activation; hyperphosphorylated tau; 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; 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 炎症在小鼠广告相关网络功能障碍中的作用(海曼博士) 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。许多研究都集中在AD的病理特征上，即淀粉样β蛋白(Aβ)斑块 沉积，tau过度磷酸化，神经纤维缠结形成，进行性丢失的神经元和 突触。最近，研究表明，免疫激活，以神经炎症和 相关的小胶质细胞激活，可能有助于经典AD病理的进展，但其作用是神经 炎症在AD患者记忆障碍中的作用尚不清楚。记忆的形成和提取 是大脑结构相互连接的网络的产物，包括海马体(HC)和前部 扣带回皮质(ACC)。使用发生AD病理(β沉积或tau)的转基因动物模型 过度磷酸化)表明在质量形成之前，HC的电活动发生了变化 淀粉样变性或变态反应症。这种类型的网络活动改变可能解释了记忆缺陷的出现 在AD进展的早期。然而，所有不同的转基因模型都显示出严重的神经炎症，无论 网络功能障碍是由于免疫反应或经典的AD病理机制尚不清楚。 研究神经炎症对记忆相关网络活动的影响有助于确定未来 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， 合并、检索)以及影响是否局限于HC或ACC，或者它们是否改变了交互作用 在这些区域之间。我们计划将我们的电生理学发现与神经炎症的标记物联系起来。 以更好地了解这些因素如何共同作用于改变网络活动。接下来，我们将考察一下 增加的神经炎症加剧了在早期病理Aβ和 Tau转基因模型。如果神经炎症导致HC和ACC中网络功能障碍的增加，这些 结果支持我们的总体假设，即NI本身正在损害记忆网络活动。这些数据将提供 AD和AD转基因患者的记忆损伤发生机制的有价值的信息 动物模型。