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.

项目概要 海马体对于学习和记忆很重要，并且非常容易受到微管聚集的影响 相关蛋白 tau (MAPT) 和神经退行性变。阿尔茨海默病中的海马和新皮质萎缩 (AD) 大脑显示退化主要发生在联合皮层的大谷氨酸能锥体神经元中 而抑制性中间神经元和初级皮质则能抵抗 MAPT 的积累和退化。然而， 导致易感神经元损伤和死亡的分子机制尚不清楚。发展更好的 了解导致兴奋性神经元易受损伤的分子机制并识别 调节 tau 介导的神经变性的途径对于阐明发病机制和 AD 的进展并确定潜在的治疗靶点。该提案的主要目标是确定途径 使兴奋性神经元容易受到 tau 蛋白积累和神经退行性变的影响，并确定潜在的治疗方法 AD 的目标。一个重要的限制是哺乳动物大脑的细胞异质性。为了克服细胞 异质性，该提案将创新性地在新鲜 AD 人脑组织和病毒中使用单细胞 RNA 测序 在 tau 蛋白病小鼠模型中翻译核糖体亲和纯化 (vTRAP)，以生成 在衰老和衰老的背景下，来自大脑脆弱和弹性区域的兴奋性和抑制性神经元 神经变性。将构建兴奋性和抑制性神经元的全局基因共表达网络 通过加权交互网络分析（WINA）和多尺度嵌入式基因共表达网络 分析（MEGENA）。 WINA 和 MEGENA 派生模块将与 AD 和最重要的驱动程序相关联 与AD最相关的模块将成为实验验证的候选目标。我们还将确定 谷氨酸和 tau 介导的毒性的独特且交叉的途径，特别是在锥体神经元中 海马体的 CA1 和 CA3 区域。细菌人工染色体 TRAP (BAC-TRAP) 报告小鼠系 与谷氨酸稳态失调模型 (EAAT2-/-) 和突变型人 tau (P301S) 结合将用于 生成海马 CA1 和 CA3 区域在疾病进展各个阶段的翻译谱。 此外，我们还将评估主要谷氨酸转运蛋白 EAAT2 在 tau 积累、反式突触中的作用 tau 扩散、免疫功能障碍和神经退行性变，及其作为遗传（病毒）治疗靶点的潜力 矢量）和化学（利鲁唑）方法。该提议将为分子机制提供新的见解 AD 中兴奋性神经元的敏感性和抑制性神经元的恢复力，确定潜在的新治疗靶点 tau 介导的神经变性，并提供谷氨酸转运蛋白 EAAT2 作为一个机制的理解 炎症和 tau 病理学传播的介质。更好地了解底层分子 AD 的机制对于开发新颖且更有效的治疗靶点至关重要。这个提议 通过揭示疾病和疾病的新机制，有可能对 AD 领域产生重大影响 确定特定的治疗靶点。