An investigation of the bidirectional relationship between tau protein propagation and neural circuit activity in mouse models of Alzheimer's disease

阿尔茨海默病小鼠模型中 tau 蛋白传播与神经回路活动之间双向关系的研究

• 批准号: 2546213
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2546213
• 关键词: investigation; bidirectional; relationship; between; tau

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder that is defined by the presenceof extracellular amyloid-beta plaques and intracellular tau-protein-containing neurofibrillary tangles inthe brain1. There are currently no effective treatments available and removing amyloid-beta has thus farbeen ineffective in clinical trials. As such, my project will focus on tau pathology and its mechanismsat the neural circuit level, with a view to elucidating the role of tau in pathoprogression of AD andinforming future circuit-level therapeutic approaches.Tau pathology in humans involves propagation of tau beginning in the entorhinal cortex, spreading tothe hippocampus, then the cerebral cortex2, and this propagation parallels the clinical stages of thedisease. However, the mechanism(s) linking protein accumulation and cognitive decline is unknown.Neuronal hyperexcitability precedes tau propagation and accumulation in disease models, and thereis evidence that neuronal activity enhances tau propagation and pathology in vivo3, although themechanism for this is not established. Furthermore, there is evidence for tau-dependent suppressionof activity and silencing of neurons4, with cell-type specific selective vulnerability5,6.The aim of this project will be to study neuronal dysfunction in the context of tau at the circuit level,employing complimentary large-scale electrophysiological (Neuropixels), two- and one-photoncalcium and voltage imaging, and behavioural studies to answer two key questions:How does activity in neural circuits affect tau propagation?How does tau propagation affect activity in neural circuits, and thereby cognition?In addressing these questions, I will investigate mechanisms for the interaction between tau andneural activity in multiple Alzheimer's disease mouse models, which will advance our understandingof the disease pathogenesis, and have relevance for therapeutic approaches based on modulatingexcitability, potentially in a cell-type specific manner.Bibliography:1. Knopman, D. S. et al. Alzheimer disease. Nat. Rev. Dis. Primer 7, 1-21 (2021).2. Busche, M. A. & Hyman, B. T. Synergy between amyloid-beta and tau in Alzheimer's disease. Nat.Neurosci. 23, 1183-1193 (2020).3. Wu, J. W. et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat.Neurosci. 19, 1085-1092 (2016).4. Busche, M. A. et al. Tau impairs neural circuits, dominating amyloid-beta effects, in Alzheimermodels in vivo. Nat. Neurosci. 22, 57-64 (2019).5. Turkes, E. & Duff, K. E. Cell-type specific selective vulnerability to pathological tau in Alzheimer'sdisease. Alzheimers Dement. 16, e043149 (2020).6. Fu, H. et al. A tau homeostasis signature is linked with the cellular and regional vulnerability ofexcitatory neurons to tau pathology. Nat. Neurosci. 22, 47-56 (2019).

阿尔茨海默病（AD）是一种使人衰弱的神经退行性疾病，其特征在于脑中存在细胞外淀粉样β斑块和细胞内含tau蛋白的神经元缠结1。目前没有有效的治疗方法，因此在临床试验中去除淀粉样蛋白β迄今无效。因此，我的项目将专注于tau蛋白的病理学及其在神经回路水平的机制，以期阐明tau蛋白在AD病理进展中的作用，并为未来的回路水平治疗方法提供信息。人类的Tau蛋白病理学涉及tau蛋白的传播，从内嗅皮层开始，扩散到海马，然后是大脑皮层2，这种传播与疾病的临床阶段平行。然而，蛋白质积累和认知能力下降之间的联系机制尚不清楚。在疾病模型中，神经元过度兴奋先于tau蛋白的传播和积累，有证据表明神经元活动增强了体内tau蛋白的传播和病理学3，尽管其机制尚未确定。此外，有证据表明tau依赖性抑制神经元的活性和沉默4，具有细胞类型特异性选择性5，6。本项目的目的是在电路水平上研究tau背景下的神经元功能障碍，采用互补的大规模电生理技术，（神经像素），双光子和单光子钙和电压成像，以及行为研究，以回答两个关键问题：神经回路中的活动如何影响tau蛋白的传播？tau蛋白的传播如何影响神经回路的活动，从而影响认知？在解决这些问题，我将研究tau蛋白和神经活动之间的相互作用机制，在多种阿尔茨海默病小鼠模型，这将推进我们的疾病发病机制的理解，并有相关的治疗方法的基础上modulatingexcitability，潜在的细胞类型特异性的方式。Knopman，D. S.等人。阿尔茨海默病。Nat. Rev. Dis. Primer 7，1-21（2021）. Busche，M. A. & Hyman，B. T.阿尔茨海默病中淀粉样蛋白β和tau蛋白之间的协同作用Nat.Neurosci. 23，1183-1193（2020）。吴，J.W.等人，Neuronal activity enhances tau propagation and tau pathology in vivo. Nat.Neurosci. 19，1085-1092（2016）中描述的。Busche，M. A. Tau impairs neural circuits，dominating amyloid-beta effects，in Alzheimer models in vivo.自然神经科学22，57-64（2019）。Turkes，E. & Duff，K. E.阿尔茨海默病中病理性tau蛋白的细胞类型特异性选择性脆弱性老年痴呆症16，e043149（2020）.6. Fu，H. tau稳态信号与兴奋性神经元对tau病理的细胞和区域脆弱性有关。自然神经科学22，47-56（2019）.