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（AD）是一种使人衰弱的神经退行性疾病，其特征是大脑中存在细胞外淀粉样斑块和细胞内含有tau蛋白的神经原纤维缠结。目前还没有有效的治疗方法，去除淀粉样蛋白在临床试验中迄今为止是无效的。因此，我的项目将专注于神经回路水平的tau病理及其机制，以阐明tau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病理包括Tau蛋白的繁殖，从内嗅皮层开始，扩散到海马体，然后是大脑皮层，这种繁殖与该疾病的临床阶段相一致。然而，连接蛋白质积累和认知能力下降的机制尚不清楚。在疾病模型中，神经元的高兴奋性先于tau的繁殖和积累，并且有证据表明，神经元活动增强了体内tau的繁殖和病理3，尽管其机制尚未确定。此外，有证据表明，tau依赖性的活性抑制和神经元沉默，具有细胞类型特异性选择性易感性5,6。该项目的目的是在回路水平上研究tau背景下的神经元功能障碍，采用互补的大规模电生理（神经像素），双光子和单光子钙和电压成像，以及行为研究来回答两个关键问题：神经回路中的活动如何影响tau的传播？tau的传播如何影响神经回路的活动，从而影响认知？为了解决这些问题，我将研究多种阿尔茨海默病小鼠模型中tau和神经活动之间相互作用的机制，这将促进我们对疾病发病机制的理解，并与基于调节兴奋性的治疗方法相关，可能以细胞类型特定的方式。Knopman, d.s.等。阿尔茨海默病。中华师范大学学报（自然科学版），第7卷第1期。Busche, m.a.和Hyman， b.t.。淀粉样蛋白- β和tau蛋白在阿尔茨海默病中的协同作用。Nat.Neurosci。[2] .中国科学：地球科学，2016,(5):391 - 391。吴俊伟等。神经元活动增强tau在体内的繁殖和tau病理。Nat.Neurosci。[j] .中国农业科学，2016,(5):391 - 391。Busche, m.a.等。在体内阿尔茨海默病模型中，Tau损害神经回路，主导淀粉样蛋白- β效应。[j] .神经科学学报，22,57-64(2019).5。Turkes， E. & Duff， K. E.阿尔茨海默病病理tau的细胞类型特异性选择性易感性。《老年痴呆症杂志》，2016,35(5):591 - 591。傅，H.等。tau稳态特征与兴奋性神经元对tau病理的细胞和区域脆弱性有关。神经科学学报，22,47-56（2019）。

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).