Neural Circuit Disruption in Freely-Behaving models of Alzheimer's Disease.

阿尔茨海默病自由行为模型中的神经回路中断。

基本信息

批准号：
10618334
负责人：
Stephen N. Gomperts
金额：
$ 76.88万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618334
关键词：
Address Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid Beta A4 Precursor Protein Amyloid beta-42 Amyloid beta-Protein Anesthesia procedures Animals Behavioral Body Temperature Brain Breeding Calcium Cells Consumption Dependence Development Early Onset Alzheimer Disease Electrodes Evaluation Exploratory Behavior Failure Frontotemporal Dementia Functional disorder Generations Genetic Goals Hippocampus Homeostasis Human Image Image Analysis Imaging technology Impairment Implant Knock-in Knowledge Late Onset Alzheimer Disease Learning Medial Microscope Modeling Monitor Multimodal Imaging Mus Nerve Degeneration Neurofibrillary Tangles Neuronal Dysfunction Neurons Pathology Physiological Physiology Research Risk Running Sampling Series Sleep System TREM2 gene Technology Time Viral Vector adeno-associated viral vector apolipoprotein E-4 awake brain cell genetic risk factor image registration indexing insight lens microscopic imaging mouse model multiphoton imaging mutant neural neural circuit neurophysiology new technology novel novel therapeutics overexpression programs risk variant serial imaging sex tau Proteins tau aggregation tau interaction technology/technique therapeutic development tool two-photon unpublished works

项目摘要

Background Summary/Abstract Determining how Aβ and tau degrade neural systems function in Alzheimer’s disease remains an essential objective. Although much has been learned from models of early onset Alzheimer’s disease (EOAD), including demonstration of aberrant neuronal activity and calcium overload in anesthetized amyloid models, the generalizability of these observations depends on two major caveats: First, it is not clear how findings under anesthesia extrapolate, particularly as the effects of amyloid and tau appear to depend on behavioral state. Second, it is not clear whether findings in EOAD models will inform understanding of late onset Alzheimer’s disease (LOAD), which is far more common and arises in association with multiple genetic risk factors. To address these issues, we will apply and integrate a series of new technologies. To extend studies to freely behaving animals and determine the behavioral state-dependence of Aβ’s impact on neuronal physiology, we will employ the Inscopix mini-microscope to monitor calcium activity together with concomitant multi-electrode recordings to assess brain oscillations. To extend studies to LOAD, we study and contrast the APP/PS1 model of EOAD with the new hAbeta.ApoE4.Trem2*R47H model of LOAD. This model, which includes knock-in of the humanized APP gene in concert with the strong risk variants APOE (humanized ApoE4) and TREM2*R47H, develops elevated levels of Aβ42 and A?40. To evaluate tau’s contribution to neuronal dysfunction and its interactions with Aβ in these amyloid models, we employ an AAV vector that expresses equimolar levels of human tau and GCaMP6f, enabling dynamic calcium imaging in tau-laden cells with the mini-microscope. To evaluate how the development of tau aggregates interacts with amyloid to affect neuronal physiology, we combine mini-microscope imaging of dynamic calcium activity with 2-photon imaging of tangles and plaques. We hypothesize that in both APP/PS1 (to model EOAD) and hAbeta.ApoE4.Trem2*R47H (to model LOAD), Aβ and tau will be associated with behavioral state-dependent changes in neuronal activity, brain oscillations, and calcium overload; that tau’s state-dependent effects will dominate those of Aβ in the EOAD and LOAD models; and that the development of tau aggregates will synergistically interact with amyloid to degrade neuronal activity. Together, these efforts will establish how Aβ and tau impair neural systems function, advancing Alzheimer’s disease modeling and informing therapeutic development.

背景摘要/摘要确定 Aβ 和 tau 如何降低阿尔茨海默氏病神经系统功能仍然至关重要尽管我们从早发性阿尔茨海默病（EOAD）模型中学到了很多东西，包括麻醉淀粉样蛋白模型中异常神经元活动和钙超载的证明，这些观察结果的普遍性取决于两个主要警告：首先，目前尚不清楚研究结果如何麻醉推断，特别是淀粉样蛋白和 tau 蛋白的作用似乎取决于行为状态。其次，目前尚不清楚 EOAD 模型的发现是否有助于理解迟发性阿尔茨海默病疾病（LOAD），这种疾病更为常见，并且与多种遗传风险因素有关。针对这些问题，我们将应用和整合一系列新技术来自由扩展研究。行为动物并确定 Aβ 对神经元生理学影响的行为状态依赖性，我们将使用 Inscopix 微型显微镜以及伴随的多电极来监测钙活性为了将研究扩展到 LOAD，我们研究并对比了 APP/PS1 模型。 EOAD 与 LOAD 的新 hAbeta.ApoE4.Trem2*R47H 模型，其中包括敲入。人源化 APP 基因与强风险变体 APOE（人源化 ApoE4）和 TREM2*R47H 相结合， Aβ42 和 A?40 水平升高评估 tau 对神经元功能障碍的影响及其影响。在这些淀粉样蛋白模型中与 Aβ 相互作用，我们采用了表达等摩尔水平的 AAV 载体人类 tau 蛋白和 GCaMP6f，能够使用微型显微镜对负载 tau 蛋白的细胞进行动态钙成像。为了评估 tau 蛋白聚集体的发育如何与淀粉样蛋白相互作用从而影响神经元生理学，我们将动态钙活性的微型显微镜成像与缠结和斑块的 2 光子成像相结合。在 APP/PS1（对于模型 EOAD）和 hAbeta.ApoE4.Trem2*R47H（对于模型 LOAD）中，Aβ 和 tau 蛋白与神经活动、大脑振荡和行为状态依赖性变化有关钙超载；在 EOAD 和 LOAD 模型中，tau 的状态依赖性效应将主导 Aβ 的效应； tau 蛋白聚集体的形成将与淀粉样蛋白协同相互作用，从而降低神经元活性。这些努力将共同确定 Aβ 和 tau 蛋白如何损害神经系统功能，从而促进阿尔茨海默病的发展疾病建模并为治疗开发提供信息。