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

基本信息

批准号：
10377486
负责人：
STEVEN M FINKBEINER
金额：
$ 64.14万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
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/10377486
关键词：
Address Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos 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 Early Onset Alzheimer Disease Epilepsy Fishes Foundations Four-dimensional Frontotemporal Dementia General Population Genetic Polymorphism Goals Hippocampus (Brain)Human Human Amyloid Precursor Protein Hyperactivity In Vitro Individual Induced pluripotent stem cell derived neurons 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 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 organoid transplantation overexpression progressive neurodegeneration relating to nervous system robotic microscopy tau Proteins tau aggregation tau mutation tau-1 transcriptome sequencing transmission process

项目摘要

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传播和神经元过度刺激性的机制，使阿尔茨海默氏病（AD）相关痴呆症中神经变性的进展（ADRD）包括由染色体21（TS21）引起的唐氏综合症（DS）。我们的研究是一致的随着RFA PAR-18-706的目标，我们将集中精力理解“对电路中Tau细胞对细胞传播的选择性细胞敏感性的基础机制”。我们研究的基础是，tau是ADRD的发病机理（例如DS）的主要罪魁祸首，因为Tau是DS大脑中神经原纤维缠结的主要组成部分，而Tau基因MAPT MAPT中的多态性则增加了TS21患者的AD和AD的风险。 ADRD中的神经病理学遵循大脑中的暂时和空间进展，越来越多的证据表明，ADRD中的逐渐神经变性是由于Tau通过连接的神经元的经突触传播引起的。除TAU外，神经元过度兴奋性可能在ADRD的早期阶段发生，有些人提出网络功能障碍可能是ADRDS神经变性的驱动力。我们将研究由于TS21引起的淀粉样蛋白前体蛋白（APP）引起的神经元活性是否改变了TS21引起的tau的透射率扩散，从而增加了神经变性的速率。我们将使用一种多学科方法来研究ADRD中发现的APP过表达如何影响TAU的传播并影响人脑电路。我们将与对照人类皮质器官或人类胎儿皮质切片进行共同培养类器官和移植的人IPSC衍生的皮质神经元（TAUP301L或TS21），并使用新颖的时间流逝，成像平台，四维机器人的机器人显微镜（4drm）来监测对神经元电路的影响。 4DRM将在数周内在人类原发性大脑切片中4D中的单个神经元的功能特性，以深入了解应用程序过表达，过度表现性和TAU传播如何相互作用以引起神经变性。纵向监测器官和人脑切片中的神经元电路的能力对于研究tau传播可能引起的缓慢退化过程至关重要。我们将使用4DRM与多元COX比例危害分析结合使用，以确定网络过度兴奋性和TAU聚集是否有害，有益或对神经元生存率无关紧要。为了完成这些体外研究，我们开发了一种体内的tauopathy整个动物模型，其中转基因斑马鱼幼虫过表达其神经系统中的人taup301l，并使用4DRM监测活动物中的神经元回路。 GFP-TAUP301L斑马鱼模型显示出P-TAU的增加，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，鱼对神经元死亡的敏感性和神经退行性的行为迹象。通过此模型，我们将研究过度兴奋性对Tau和Tau聚集的影响体内tau传播的机理。通过了解TAU传播的机制，我们可以制定策略来阻止神经病理学的传播以减缓AD的发展。