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： 阿尔茨海默氏病（AD）从早期到后期到后期的毁灭性进展 刺激搜索药物，以防止这种进展，并寻求可以治疗症状的药物 即使面对下降，记忆力丧失也可以改善生活质量。我们假设确定效果 啮齿动物海马中重要局部电路的动态活性的AD进展 已知的空间内存的电路将产生脑功能障碍的早期指标，这更相关 为了发现将在人类中起作用的药物，尤其是考虑到所有哺乳动物中该电路的保护。 海马内的CA3和CA1锥体细胞（或“位置细胞”）的发射模式响应并编码 空间表示。我们以前对老年大鼠体内电生理研究研究，一个模型 敏感认知障碍（AMCI）证明我们能够量化年龄和新颖的特定效果 CA3和CA1上的药物放置细胞动力学和空间记忆（Robitsek 2015）。在此应用程序中，我们 建议使用令人兴奋的新大鼠模型进行AD（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中病理的进展如何与 随着时间的推移，海马放置细胞动力学的变化。此外，我们将探测GABA-的急性影响 受体负变构调节剂对通常活性alpha5亚基的选择性含有受体的受体 位置单元动力学上的内存增强器。我们将使用高密度在体内电生理学进行监测 在这个新颖的大鼠转基因模型中，“位置细胞”功能随着年龄的增长，提出以下问题：三何时 突触电路变得异常吗？是早期灾难与P-Tau和神经原纤维缠结有关 编队，还是独立的？海马三突触电路中有一个不同的部分 疾病进展过程中脆弱？最后，我们可以开始解释负面的机制 活性抑制受体的变构调节剂会导致空间记忆增强。我们预料到这一点 这些研究的完成将确定Ca3＆Ca1在AD大鼠中的活性特征，有时 导致记忆和神经病理学传播的损失。这些研究将是阐明的第一步 人类App695和PS1的神经回路功能障碍的发作下降的潜在空间记忆下降 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 改进广告管理中记忆增强子急性管理评估的基金会。