Mechanisms of Susceptibility of Excitatory Neurons to Tau Pathology and Neurodegeneration in Alzheimer's disease

阿尔茨海默病中兴奋性神经元对 Tau 病理学和神经变性的易感性机制

• 批准号: 9913057
• 负责人: Ana C. Pereira
• 金额: $ 78.68万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9913057
• 关键词: Acceleration; Affinity Chromatography; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease risk; American; Atrophic; Autopsy; Bacterial Artificial Chromosomes; Behavioral; Brain; Brain region; Cells; Cessation of life; Chemicals; Cognitive deficits; Data; Development; Disease; Disease Progression; Excitatory Amino Acid Transporter 2; Expression Profiling; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Glutamate Transporter; Glutamates; Goals; Heterogeneity; Hippocampus (Brain); Human; Immune System Diseases; Impaired cognition; Impairment; Inflammation; Inflammation Mediators; Internal Ribosome Entry Site; Interneurons; Learning; MAPT gene; Mediating; Memory; Memory impairment; Messenger RNA; Methodology; Modeling; Molecular; Motor Cortex; Mus; Neocortex; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathology; Pathway Analysis; Pathway interactions; Physiological; Play; Polyribosomes; Population; Predisposition; Prefrontal Cortex; Reporter; Resected; Resistance; Ribosomes; Riluzole; Role; Societies; Suspensions; Synapses; Tauopathies; Techniques; Testing; Toxic effect; Translating; Treatment Efficacy; Validation; Viral; Viral Vector; Visual Cortex; adeno-associated viral vector; age related; association cortex; brain tissue; cell type; economic impact; effective therapy; entorhinal cortex; excitatory neuron; experimental study; hippocampal pyramidal neuron; human disease; hyperphosphorylated tau; indexing; induced pluripotent stem cell; inhibitory neuron; innovation; insight; knock-down; mouse model; mutant; neocortical; neural circuit; neuroinflammation; neuron loss; neurotoxicity; new therapeutic target; novel; overexpression; psychologic; psychosocial; public health relevance; resilience; single cell sequencing; single-cell RNA sequencing; tau Proteins; tau aggregation; tau mutation; therapeutic target; transcriptomics; uptake

Project summary The hippocampus is important for learning and memory and is highly susceptible to aggregation of microtubule- associated protein tau (MAPT) and neurodegeneration. Hippocampal and neocortical atrophy in Alzheimer’s disease (AD) brains demonstrates degeneration predominantly in large glutamatergic pyramidal neurons in association cortices while inhibitory interneurons and primary cortices are resistant to MAPT accumulation and degeneration. However, the molecular mechanisms that cause damage and death of susceptible neurons are not understood. Developing a better understanding of the molecular mechanisms causing vulnerability of excitatory neurons to damage and identifying pathways that regulate tau-mediated neurodegeneration will be essential to unraveling the pathogenesis and progression of AD and identifying potential therapeutic targets. The primary goal of this proposal is to identify pathways that make excitatory neurons susceptible to tau accumulation and neurodegeneration, and identify potential therapeutic targets for AD. One important limitation is the cellular heterogeneity of the mammalian brain. To overcome the cellular heterogeneity, this proposal will innovatively use single cell RNA sequencing in fresh AD human brain tissue and viral translating ribosome affinity purification (vTRAP) in a mouse model of tauopathy to generate transcriptional profiles of excitatory and inhibitory neurons from vulnerable and resilient regions of the brain in the context of aging and neurodegeneration. Global gene co-expression networks for excitatory and inhibitory neurons will be constructed through Weighted Interaction Network Analysis (WINA) and Multiscale Embedded Gene co-Expression Network Analysis (MEGENA). WINA and MEGENA derived modules will then be associated with AD and the top key drivers of the modules most associated with AD will become the candidate targets for experimental validation. We will also identify distinct and intersecting pathways from glutamate and tau mediated toxicities specifically in the pyramidal neurons of CA1 and CA3 regions of the hippocampus. Bacterial artificial chromosome TRAP (BAC-TRAP) reporter mouse lines in conjunction with models of glutamate dyshomeostasis (EAAT2-/-) and mutant human tau (P301S) will be used to generate translational profiles of CA1 and CA3 regions of the hippocampus at various stages of disease progression. Further, we will also evaluate the role of EAAT2, the major glutamate transporter, in tau accumulation, trans synaptic tau spread, immune dysfunction and neurodegeneration, and its potential as a therapeutic target using genetic (viral vector) and chemical (riluzole) approaches. This proposal will provide novel insights into the molecular mechanisms of excitatory neuronal susceptibility and resilience of inhibitory neurons in AD, identify potential new therapeutic targets for tau-mediated neurodegeneration and provide a mechanistic understanding of glutamate transporter EAAT2 as a mediator of inflammation and spread of tau pathology. A better understanding of the underlying molecular mechanisms of AD is crucial for the development of novel and more effective therapeutic targets. This proposal has the potential to make a significant impact to the field of AD by uncovering novel mechanisms of disease and identification of specific therapeutic targets.

项目摘要 海马对于学习和记忆很重要，并且非常容易受到微管的聚集 相关的蛋白质tau（MAPT）和神经变性。阿尔茨海默氏病的海马和新皮质萎缩 （AD）大脑在缔合皮层中的大谷氨酸能金字塔神经元中主要证明了变性 而抑制性中间神经元和原发性皮质对MAPT积累和变性具有抗性。但是， 不了解引起易感神经元损害和死亡的分子机制。发展更好 了解导致兴奋神经元脆弱性损害和识别的分子机制 调节tau介导的神经变性的途径对于揭示发病机理和 AD的进展并确定潜在的治疗靶标。该提议的主要目标是确定途径 这使兴奋性神经元易受tau积累和神经变性，并确定潜在的治疗 AD的目标。一个重要的限制是哺乳动物大脑的细胞异质性。克服细胞 异质性，该建议将在新鲜的AD人脑组织和病毒中创新使用单细胞RNA测序 在tauopathy的小鼠模型中翻译核糖体亲和力纯化（VTRAP），以生成 在衰老和 神经变性。将构建用于兴奋和抑制神经元的全球基因共表达网络 通过加权交互网络分析（WINA）和多尺度嵌入基因共表达网络 分析（Megena）。然后，Wina和Megena衍生的模块将与广告相关联，并且是主要的主要驱动力 与AD相关的模块将成为实验验证的候选目标。我们还将确定 与谷氨酸和TAU介导的毒性的不同和相交的途径特别是在锥体神经元中的毒性 海马的CA1和CA3区域。细菌人造染色体陷阱（BAC-TRAP）记者小鼠系列 与谷氨酸dyshomeostasis（EAAT2 - / - ）和突变人类Tau（P301S）的模型的联系将用于 在疾病进展的各个阶段，产生海马的CA1和CA3区域的翻译谱。 此外，我们还将评估主要谷氨酸转运蛋白EAAT2在Tau积累，反式突触的作用 tau扩散，免疫功能障碍和神经变性，其作为治疗靶标的潜力（病毒 载体）和化学（riluzole）方法。该建议将提供有关分子机制的新见解 AD中抑制性神经元的兴奋性神经元敏感性和弹性，确定潜在的新治疗靶点 tau介导的神经退行性创变，并提供对谷氨酸转运蛋白EAAT2的机械理解 炎症和tau病理传播的介体。更好地理解基础分子 AD的机制对于开发新颖和更有效的治疗靶标至关重要。这个建议 通过发现新型疾病机制和 识别特定的治疗靶标。