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)是一种衰弱的神经退行性疾病，其定义是大脑中存在细胞外淀粉样β斑块和细胞内含有tau蛋白的神经原纤维缠结1。目前还没有有效的治疗方法，到目前为止，去除淀粉样β蛋白在临床试验中是无效的。因此，我的项目将集中在tau病理及其在神经电路水平的机制，以期阐明tau在AD的病理进展中的作用，并为未来的电路水平的治疗方法提供信息。人类的tau病理涉及tau的传播，从内嗅皮层开始，扩散到海马体，然后是大脑皮质2，这种传播与疾病的临床阶段平行。然而，将蛋白质积累和认知能力下降联系在一起的机制(S)尚不清楚。在疾病模型中，神经元的超兴奋性先于tau的增殖和积累，并且有证据表明，神经元活动促进了活体3中tau的增殖和病理，尽管这一机制尚未建立。此外，有证据表明tau依赖抑制神经元的活动和沉默4，具有细胞类型的选择性易损性5.本项目的目的是在电路水平研究tau的神经元功能障碍，采用补充的大规模电生理(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中的活动，从而影响认知？在回答这些问题时，我将研究tau与神经活动之间的相互作用的机制，这将促进我们对疾病、发病机制和认知的理解并与基于调节兴奋性的治疗方法相关，潜在地以细胞类型特定的方式。参考文献：1。阿尔茨海默病。纳特。迪斯牧师。引子7，1-21(2021).阿尔茨海默病中淀粉样β蛋白和tau蛋白之间的协同作用。自然，神经科。23、1183-1193(2020)。Wu，J.W.等人。在体内，神经元的活动增强了tau的繁殖和tau的病理。自然，神经科。19,1085-1092(2016).Busche，M.A.等人。在体内的阿尔茨海默病模型中，tau损害神经回路，主导淀粉样β效应。纳特。神经科。22，57-(2019)。5。阿尔茨海默病中对病理tau的细胞类型特异性选择性易感性。老年痴呆症。16，e043149(2020)。6.Fu，H.等人。Tau的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。纳特。神经科。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).