Contributions of cell type and exosome signaling to prodromal synaptic and circuit changes in Alzheimer's Disease models

细胞类型和外泌体信号传导对阿尔茨海默病模型中前驱期突触和回路变化的贡献

• 批准号: 10540117
• 负责人: Kristin Kay Baldwin
• 金额: $ 256.01万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540117
• 关键词: Address; Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Astrocytes; Biological Assay; Biological Markers; Brain; Catalogs; Cell Line; Cell physiology; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Collection; Disease; Disease Progression; Early Diagnosis; Early treatment; Event; Female; Gender; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genetic study; Genome; Genotype; Human; Human Genetics; Image; Impaired cognition; Individual; Knowledge; Malignant Neoplasms; Measures; Mediating; Methods; Microglia; Molecular Profiling; Monitor; Mutation; Neuroglia; Neurons; Pathogenicity; Pathologic; Patients; Persons; Play; Population; Predisposition; Property; Proteins; Proteomics; Protocols documentation; RNA; Risk; Role; Sampling; Signal Transduction; Source; Susceptibility Gene; Synapses; Testing; Untranslated RNA; Variant; aged; base; brain cell; brain tissue; candidate marker; cell type; cellular engineering; cognitive function; exosome; extracellular vesicles; induced pluripotent stem cell; intercellular communication; male; molecular imaging; nervous system disorder; neural circuit; new technology; novel; presenilin; protective allele; response; risk variant; tau Proteins; therapeutic target; transcriptome sequencing; transcriptomics; vesicular release

Alzheimer’s Disease (AD) is characterized by loss of synapses, resulting in decline of cognitive function. The pathology of AD is increasingly recognized to involve neuronal interactions with other brain cell types, notably microglia and astrocytes. Extracellular vesicles (EVs) are secreted by all cells in the brain, and carry protein and RNA cargo. EVs have the capacity to signal from donor to recipient cells within brain tissue and modify cell functions, as shown in cancers and multiple neurological diseases. EV propagation of pathologic proteins between cells in the brain is a strong candidate mechanism underlying at least some aspects of AD pathology, suggesting that distinct EV cargos may not only serve as biomarkers for disease but also directly induce vulnerability to or protection from pathologic disease states. Yet, little is known about EV cargo diversity and bioactivity from key brain cell types implicated in AD. Furthermore, the impact of genetic susceptibility loci or other factors such as gender has not been determined with respect to EV content, EV bioactivity or variation in neuronal responses to EVs. To overcome these barriers, we propose to use iPSCs and direct reprogramming to generate purified cultures of human neurons, astrocytes and microglia from iPSCs that vary by their AD-related genetic background or expected susceptibility. Because variation at APOE has a strong effect on both AD risk (APOE4) and protection (APOE2) we will profile EV cargos of EVs from isogenic iPSCs of each APOE genotype using state-of-the-art proteomic and RNA-Seq methods. In parallel, we will address the functional consequences of EV bioactivity on human induced neurons with two sensitive readouts: imaging neuronal connectivity and synaptic dynamics and unbiased transcriptomic profiling. These collaborative studies will establish a novel catalog of cell-type based profiles of EV cargo diversity and signaling bioactivity. Comparing EV contents from pathologic risk and protective variants has the potential to uncover novel mechanisms related to cell-to-cell spread of pathogenic or protective signals, and identify candidate biomarkers to test in clincal samples of human AD patients.

阿尔茨海默氏病（AD）的特征是突触丧失，导致认知功能下降。这 AD的病理越来越多地被认为涉及与其他脑细胞类型的神经元相互作用，特别是 小胶质细胞和星形胶质细胞。细胞外蔬菜（EV）均由大脑中的所有细胞分泌，并携带蛋白质和 RNA货物。电动汽车具有从供体到受体细胞内脑组织内的受体细胞并修改细胞的能力 功能，如癌症和多种神经系统疾病所示。病理蛋白的EV传播 大脑中的细胞之间是至少AD病理学的某些方面的强大候选机制， 暗示不同的EV货物不仅可以用作疾病的生物标志物，而且还可以直接诱导 对病理疾病状态的脆弱性或保护。然而，关于电动汽车货物多样性和 AD中实施的关键脑细胞类型的生物活性。此外，遗传易感性区域或 其他因素（例如性别）尚未确定EV含量，EV生物活性或变化 神经元对电动汽车的反应。为了克服这些障碍，我们建议使用IPSC并直接重新编程 产生来自IPSC的人类神经元，星形胶质细胞和小胶质细胞的纯化培养物，它们因其广告相关而异 遗传背景或预期敏感性。因为APOE的变化对两种AD风险都有很强的影响 （APOE4）和保护（APOE2）我们将从每种APOE基因型的等源IPSC中介绍电动汽车的EV Cargos 使用最先进的蛋白质组学和RNA-seq方法。同时，我们将解决功能后果 具有两个敏感读数的人类诱导神经元的EV生物活性：成像神经元连通性和 突触动力学和公正的转录组分析。这些协作研究将建立小说 基于细胞类型的EV货物多样性和信号生物活性的基于细胞类型的目录。比较来自 病理风险和受保护的变体有可能发现与细胞到细胞有关的新型机制 传播致病或受保护的信号，并鉴定候选生物标志物以在人类的crincal样品中进行测试 广告患者。