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:
  • 金额:
    $ 76.88万
  • 依托单位:
  • 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

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.
背景概要/摘要 确定Aβ和tau蛋白如何降低阿尔茨海默病中的神经系统功能仍然是一个重要的问题。 objective.尽管已经从早发性阿尔茨海默病(EOAD)模型中了解了很多,包括 在麻醉的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的警告:首先,目前还不清楚研究结果是如何根据 麻醉外推,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模型的发现是否会为晚发性阿尔茨海默病的理解提供信息 这种疾病(LOAD)更为常见,与多种遗传风险因素有关。到 针对这些问题,我们将应用和集成一系列新技术。将研究扩展到自由 行为的动物,并确定行为状态依赖的Aβ的影响神经元生理学,我们 将使用Insopix微型显微镜监测钙活性以及伴随的多电极 记录来评估脑震荡。为了将研究扩展到LOAD,我们研究和对比了APP/PS1模型 用LOAD的新hAbeta.ApoE4.Trem2* R47 H模型进行EOAD的研究。这种模式,其中包括敲入的 人源化APP基因与强风险变体APOE(人源化ApoE 4)和TREM 2 * R47 H一致, Aβ42和A?40.为了评估tau蛋白对神经元功能障碍的贡献及其在神经元损伤中的作用, 在这些淀粉样蛋白模型中,我们采用了一种AAV载体,该载体表达等摩尔水平的 人tau蛋白和GCaMP 6 f,使动态钙成像的tau负载细胞的微型显微镜。到 为了评估tau聚集体的形成如何与淀粉样蛋白相互作用以影响神经元生理学,我们 将动态钙活性的微型显微镜成像与缠结和斑块的双光子成像联合收割机结合。我们 假设在APP/PS1(模拟EOAD)和hAbeta.ApoE4.Trem2* R47 H(模拟LOAD)中,Aβ和 tau蛋白将与神经元活动、脑振荡和神经元活动中的行为状态依赖性变化相关。 钙超载;在EOAD和LOAD模型中,tau的状态依赖性效应将主导Aβ的状态依赖性效应; 并且tau聚集体的形成将与淀粉样蛋白协同相互作用以降低神经元活性。 总之,这些努力将确定Aβ和tau蛋白如何损害神经系统功能, 疾病建模和告知治疗发展。

项目成果

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Stephen N. Gomperts其他文献

Imaging the Role of Amyloid in PD Dementia and Dementia with Lewy Bodies
Impaired hippocampal circuit function underlying memory encoding and consolidation precede robust Aβ deposition in a mouse model of alzheimer’s disease
在阿尔茨海默病小鼠模型中,记忆编码和巩固的海马回路功能受损先于 Aβ 大量沉积。
  • DOI:
    10.1038/s41598-025-05653-2
  • 发表时间:
    2025-07-01
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Hanyan Li;Zhuoyang Zhao;Aline Fassini;Han K. Lee;Reese J. Green;Stephen N. Gomperts
  • 通讯作者:
    Stephen N. Gomperts

Stephen N. Gomperts的其他文献

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{{ truncateString('Stephen N. Gomperts', 18)}}的其他基金

Imaging epigenetic dysregulation in the Lewy body dementias with [11C]Martinostat
使用 [11C]Martinostat 对路易体痴呆的表观遗传失调进行成像
  • 批准号:
    10661239
  • 财政年份:
    2023
  • 资助金额:
    $ 76.88万
  • 项目类别:
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。
  • 批准号:
    10448669
  • 财政年份:
    2022
  • 资助金额:
    $ 76.88万
  • 项目类别:
Imaging Epigenetic Mechanisms in the Lewy Body Dementias with [11C]Martinostat
使用 [11C]Martinostat 对路易体痴呆的表观遗传机制进行成像
  • 批准号:
    10461316
  • 财政年份:
    2021
  • 资助金额:
    $ 76.88万
  • 项目类别:
Impact of Amyloid Beta on Hippocampal Neurophysiology and Calcium Activity across the Sleep-Wake Cycle
β 淀粉样蛋白对睡眠-觉醒周期中海马神经生理学和钙活性的影响
  • 批准号:
    9916679
  • 财政年份:
    2017
  • 资助金额:
    $ 76.88万
  • 项目类别:
Impact of Amyloid Beta on Hippocampal Neurophysiology and Calcium Activity across the Sleep-Wake Cycle
β 淀粉样蛋白对睡眠-觉醒周期中海马神经生理学和钙活性的影响
  • 批准号:
    9381672
  • 财政年份:
    2017
  • 资助金额:
    $ 76.88万
  • 项目类别:
PET imaging of hyperphosphorylated tau differentiates PSP and CBD from PD
过度磷酸化 tau 蛋白的 PET 成像可区分 PSP 和 CBD 与 PD
  • 批准号:
    8808816
  • 财政年份:
    2014
  • 资助金额:
    $ 76.88万
  • 项目类别:
PET imaging of hyperphosphorylated tau differentiates PSP and CBD from PD
过度磷酸化 tau 蛋白的 PET 成像可区分 PSP 和 CBD 与 PD
  • 批准号:
    8927088
  • 财政年份:
    2014
  • 资助金额:
    $ 76.88万
  • 项目类别:
Ventral Tegmental Area and Hippocampal Interactions in Reinforced Spatial Learnin
强化空间学习中的腹侧被盖区和海马相互作用
  • 批准号:
    8078180
  • 财政年份:
    2008
  • 资助金额:
    $ 76.88万
  • 项目类别:
Ventral Tegmental Area and Hippocampal Interactions in Reinforced Spatial Learnin
强化空间学习中的腹侧被盖区和海马相互作用
  • 批准号:
    8269135
  • 财政年份:
    2008
  • 资助金额:
    $ 76.88万
  • 项目类别:
Ventral Tegmental Area and Hippocampal Interactions in Reinforced Spatial Learnin
强化空间学习中的腹侧被盖区和海马相互作用
  • 批准号:
    7470832
  • 财政年份:
    2008
  • 资助金额:
    $ 76.88万
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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