Cell and Network Disruptions and Associated Pathogenenesis in Tauopathy and Down Syndrome

Tau 蛋白病和唐氏综合症的细胞和网络破坏及相关发病机制

• 批准号: 9974319
• 负责人: STEVEN M FINKBEINER
• 金额: $ 66.32万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9974319
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Animals; Behavioral; Biological Assay; Brain; Cells; Chromosome 21; Coculture Techniques; Cognitive deficits; Complement; Dementia; Down Syndrome; Epilepsy; Expression Profiling; Fishes; Foundations; Four-dimensional; Frontotemporal Dementia; General Population; Genetic Polymorphism; Goals; Hippocampus (Brain); Human; Human Amyloid Precursor Protein; Hyperactive behavior; In Vitro; Individual; Interneurons; Label; Larva; Long-Term Potentiation; MAPT gene; Mediating; Methods; Modeling; Molecular; Monitor; Nerve Degeneration; Nervous system structure; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Optics; Organoids; Pathogenesis; Pathogenicity; Pathology; Patients; Physiologic pulse; Physiological; Presenile Alzheimer Dementia; Prevalence; Process; Property; Protein Overexpression; Risk; Rodent; Role; Seizures; Senile Plaques; Slice; Synapses; System; Tauopathies; Technology; Testing; Time; Tissues; Transgenic Organisms; Transplantation; Trisomy; Zebrafish; brain circuitry; demented; driving force; early onset; fetal; hazard; hyperphosphorylated tau; imaging platform; in vivo; induced pluripotent stem cell; innovation; insight; interdisciplinary approach; knock-down; network dysfunction; neural circuit; neuron loss; neuronal circuitry; neuronal survival; neuropathology; novel; overexpression; progressive neurodegeneration; relating to nervous system; robotic microscopy; tau Proteins; tau aggregation; tau mutation; tau-1; transcriptome sequencing; transmission process

The goal of our studies is to better understand the mechanisms by which tau transmission and neuronal hyperexcitability drive the progression of neurodegeneration in Alzheimer's Disease (AD) Related Dementias (ADRD) that include Down Syndrome (DS) caused by trisomy of chromosome 21 (Ts21). Our studies are in line with the goals of RFA PAR-18-706 because we will focus on understanding “mechanisms underlying selective cell sensitivity to tau cell-to-cell spread in circuitry.” The foundation of our studies is that tau is a prime culprit in pathogenesis of ADRDs such as DS because tau is a major component of neurofibrillary tangles in DS brains and polymorphisms in the tau gene MAPT increase risk of AD and AD in Ts21 patients. Neuropathology in ADRD follows a temporal and spatial progression in brain, and there is growing evidence that the progressive neurodegeneration in ADRD is due to transsynaptic spread of tau via connected neurons. In addition to tau, neuronal hyperexcitability can occur at early stages of ADRD, and some have proposed that network dysfunction may be a driving force for neurodegeneration in ADRDs. We will investigate if altered neuronal activity due to overexpression of amyloid precursor protein (APP) caused by Ts21 contributes to the transsynaptic spread of tau, increasing the rate of neurodegeneration. We will use a multidisciplinary approach to study how APP overexpression found in ADRDs affects transmission of tau and impacts human brain circuitry. We will co-culture organoids and transplant human iPSC-derived cortical neurons from ADRD patients (tauP301L or Ts21) with control human cortical organoids or human fetal cortical slices and monitor the impact on neuronal circuits using a novel time lapse, imaging platform, four-dimensional robotic microscopy (4DRM). 4DRM will track functional properties of individual neurons in 4D in human primary brain slices over weeks, to give insight into how APP overexpression, hyperexcitability, and tau transmission interact to cause neurodegeneration. The ability to monitor neuronal circuitry in organoids and human brain slices longitudinally is innovative and critical in studying the slow degenerative processes that may be induced by tau transmission. We will use 4DRM in combination with multivariate Cox proportional hazards analysis to determine if network hyperexcitability and tau aggregation is detrimental, beneficial or inconsequential towards neuronal survival. To complement these in vitro studies, we developed an in vivo whole animal model of tauopathy in which transgenic zebrafish larvae overexpress human tauP301L in their nervous system and use 4DRM to monitor neuronal circuitry in the living animals. The GFP-tauP301L zebrafish model shows increased p-tau but no overt neuronal dysfunction, or neurodegeneration. When hyperexcitability is induced, the fish display sensitivity to neuronal death and behavioral signs of neurodegeneration. With this model, we will investigate the effect of hyperexcitability on aggregation of tau and mechanisms of tau transmission in vivo. By understanding mechanisms of tau transmission, we can develop strategies to block spread of neuropathology to slow the progression of AD.

我们研究的目的是更好地了解 tau 蛋白传递和神经元过度兴奋驱动阿尔茨海默病 (AD) 相关痴呆症神经退行性病变进展的机制 (ADRD)，包括由 21 号染色体 (Ts21) 三体性引起的唐氏综合症 (DS)。我们的学业是一致的 符合 RFA PAR-18-706 的目标，因为我们将重点了解“选择性细胞对电路中 tau 细胞间扩散的敏感性的潜在机制”。我们研究的基础是，tau 是 DS 等 ADRD 发病机制的罪魁祸首，因为 tau 是 DS 大脑中神经原纤维缠结的主要组成部分，并且 tau 基因 MAPT 的多态性会增加 Ts21 患者患 AD 和 AD 的风险。 ADRD 的神经病理学遵循大脑的时间和空间进展，并且越来越多的证据表明 ADRD 的进行性神经变性是由于 tau 蛋白通过连接的神经元进行突触扩散所致。除了 tau 蛋白外，ADRD 早期也可能出现神经元过度兴奋，一些人提出网络功能障碍可能是 ADRD 神经退行性变的驱动力。我们将研究 Ts21 引起的淀粉样前体蛋白 (APP) 过度表达导致的神经元活动改变是否会导致 tau 蛋白跨突触扩散，从而增加神经变性的发生率。我们将采用多学科方法来研究 ADRD 中的 APP 过度表达如何影响 tau 蛋白的传输并影响人脑回路。我们将共培养类器官，并将来自 ADRD 患者（tauP301L 或 Ts21）的人类 iPSC 衍生的皮质神经元与对照人类皮质类器官或人类胎儿皮质切片一起移植，并使用新型延时、成像平台、四维机器人显微镜 (4DRM) 监测对神经元回路的影响。 4DRM 将在数周内追踪人类原代脑切片中 4D 单个神经元的功能特性，以深入了解 APP 过度表达、过度兴奋和 tau 蛋白传递如何相互作用导致神经退行性变。纵向监测类器官和人脑切片中的神经元回路的能力对于研究 tau 传输可能引起的缓慢退行性过程而言是创新且至关重要的。我们将使用 4DRM 与多变量 Cox 比例风险分析相结合，以确定网络过度兴奋性和 tau 聚集对神经元存活是否有害、有益或无关紧要。为了补充这些体外研究，我们开发了 tau 蛋白病的体内整体动物模型，其中转基因斑马鱼幼虫在其神经系统中过度表达人 tauP301L，并使用 4DRM 监测活体动物的神经元回路。 GFP-tauP301L 斑马鱼模型显示 p-tau 增加，但没有明显的神经元功能障碍或神经变性。当诱发过度兴奋时，鱼表现出对神经元死亡和神经退行性变行为迹象的敏感性。通过这个模型，我们将研究过度兴奋对 tau 蛋白聚集的影响 tau蛋白在体内的传递机制。通过了解 tau 蛋白传播机制，我们可以制定策略来阻止神经病理学的传播，从而减缓 AD 的进展。