Age-Related Changes in Neural Network Activity and Tau in a rat model of Alzheimer's Disease

阿尔茨海默病大鼠模型中神经网络活动和 Tau 蛋白与年龄相关的变化

• 批准号: 9530214
• 负责人: David H Farb
• 金额: $ 24.73万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9530214
• 关键词: Acute; Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Bioavailable; Biological Neural Networks; Blood; Brain; Cells; Chronic; Custom; Data; Data Analyses; Decision Making; Deposition; Deterioration; Disease Management; Disease Marker; Disease Progression; Dose; Early Onset Familial Alzheimer' s Disease; Electrophysiology (science); Enhancers; Environment; Exhibits; Experimental Designs; Food; Foundations; Functional disorder; Future; GABA-A Receptor; Gene Expression; Genes; Hippocampus (Brain); Home environment; Human; Human Pathology; Hyperactive behavior; Impaired cognition; Impairment; Implant; Mammals; Measures; Memory; Memory Loss; Memory impairment; Methods; Microelectrodes; Modeling; Molecular; Monitor; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Neuromodulator; Oral; Pathologic; Pathology; Patients; Pattern; Pharmaceutical Preparations; Plasma; Procedures; Pyramidal Cells; Quality of life; Rattus; Reproducibility; Research Personnel; Rodent; Running; Senile Plaques; Series; System; Technology; Therapeutic; Time; Tissues; Transgenic Model; Transgenic Organisms; Treatment Efficacy; Work; age related; aged; amnestic mild cognitive impairment; base; brain dysfunction; computerized data processing; density; gene product; improved; in vivo; male; mild cognitive impairment; morris water maze; mutant; neural circuit; neurofibrillary tangle formation; neuropathology; novel; presenilin-1; presenilin-2; prevent; receptor; spatial memory; symptom treatment; tau Proteins; tau-1; tool

Abstract: The devastating progression of Alzheimer's disease (AD) from the early prodromal to late stages has stimulated a search for drugs that prevent this progression and a quest for drugs that can treat the symptoms of memory loss to improve the quality of life even in the face of decline. We hypothesize that determining the effect of AD progression on the dynamic activity of important local circuits in the rodent hippocampus, the tri-synaptic circuit known to underlie spatial memory, will produce an early indicator of brain dysfunction that is more relevant for the discovery of drugs that will work in humans, especially given the conservation of this circuit in all mammals. The firing patterns of CA3 & CA1 pyramidal cells (or “place cells”) within the hippocampus respond to and encode spatial representations. Our previous in vivo electrophysiological study of aged impaired rats, a model for amnestic cognitive impairment (aMCI), demonstrated that we are able to quantify age and novelty specific effects of drugs on CA3 & CA1 place cell dynamics and on spatial memory (Robitsek 2015). In this application, we propose to use an exciting new rat model for AD (TgF344-AD) that displays amyloid plaques and, importantly, neurofibrillary tangles to determine how the progression of pathology seen in human patients is associated with alterations in hippocampal place cell dynamics over time. In addition, we will probe the acute effects of a GABA- A receptor negative allosteric modulator selective for tonically active alpha5 subunit containing receptors that is a memory enhancer on place cell dynamics. We will use high density in vivo electrophysiology for monitoring “place cell” function with age in this novel rat transgenic model to ask the following questions: When does the tri- synaptic circuit become disturbed? Is early disturbance associated with P-tau and neurofibrillary tangle formation, or is it independent? Is there a distinct part of the hippocampal tri-synaptic circuitry that is most vulnerable during disease progression? And finally, can we begin to explain the mechanism by which a negative allosteric modulator of active inhibitory receptors results in spatial memory enhancement. We anticipate that completion of these studies will identify the activity profile of CA3 & CA1 place cells in AD rats that eventually leads to a loss in memory and spread of neuropathology. These studies will be a first step toward elucidating the onset of neural circuitry dysfunction underlying spatial memory decline over a human APP695 and PS1 background that exhibits progressive neurofibrillary tangles and cognitive impairment and will provide a foundation for improved assessment for acute administration of memory enhancers in AD management.

抽象的： 阿尔茨海默病（AD）从早期前驱阶段到晚期的破坏性进展已经 刺激了对阻止这种进展的药物的寻找，以及对可以治疗症状的药物的探索 即使面对记忆力减退，也能提高生活质量。我们假设确定效果 AD 进展对啮齿动物海马重要局部回路（三突触）动态活动的影响 已知是空间记忆基础的电路将产生更相关的大脑功能障碍的早期指标 发现对人类有效的药物，特别是考虑到该电路在所有哺乳动物中都是保守的。 海马内 CA3 和 CA1 锥体细胞（或“位置细胞”）的放电模式响应并编码 空间表示。我们之前对老年受损大鼠进行的体内电生理研究，这是一个模型 遗忘性认知障碍（aMCI），证明我们能够量化年龄和新奇事物的具体影响 药物对 CA3 和 CA1 位置细胞动力学和空间记忆的影响 (Robitsek 2015)。在这个应用程序中，我们 建议使用一种令人兴奋的新 AD 大鼠模型 (TgF344-AD)，该模型显示淀粉样斑块，重要的是， 神经原纤维缠结以确定人类患者的病理进展与 海马位置细胞动力学随时间的变化。此外，我们将探讨 GABA- 的急性影响 一种受体负变构调节剂，对包含受体的补强活性 α5 亚基有选择性 位置细胞动力学的记忆增强剂。我们将使用高密度体内电生理学进行监测 在这种新型大鼠转基因模型中，“位置细胞”随着年龄的增长而发挥作用，以提出以下问题：三 突触回路受到干扰？早期紊乱与 P-tau 和神经原纤维缠结有关吗 是形成的，还是独立的？海马三突触回路中是否有一个最重要的独特部分？ 在疾病进展过程中容易受到伤害吗？最后，我们能否开始解释负面影响的机制？ 活性抑制受体的变构调节剂导致空间记忆增强。我们预计 这些研究的完成将确定 AD 大鼠中 CA3 和 CA1 位置细胞的活性特征，最终 导致记忆丧失和神经病理学的传播。这些研究将是阐明这一问题的第一步 人类 APP695 和 PS1 空间记忆衰退背后的神经回路功能障碍的发生 表现出进行性神经原纤维缠结和认知障碍的背景，并将提供 为改进 AD 管理中记忆增强剂的急性管理评估奠定了基础。