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.

阿尔茨海默病（Alzheimer's Disease，AD）是一种以突触缺失为特征的疾病，其主要表现为认知功能的减退。的 越来越多的人认识到AD的病理学涉及神经元与其他脑细胞类型的相互作用， 小胶质细胞和星形胶质细胞。细胞外囊泡（EV）由脑中的所有细胞分泌，并携带蛋白质和 RNA货物。EV能够在脑组织内从供体细胞向受体细胞发出信号， 功能，如癌症和多种神经系统疾病所示。病理蛋白的EV传播 是AD病理学至少某些方面的潜在的强有力的候选机制， 这表明不同的EV货物不仅可以作为疾病的生物标志物， 易受病理性疾病状态的伤害或保护。然而，人们对电动汽车货物的多样性知之甚少， 与AD有关的关键脑细胞类型的生物活性。此外，遗传易感性位点或 其他因素如性别尚未确定EV含量、EV生物活性或 神经元对EV的反应。为了克服这些障碍，我们建议使用iPSC和直接重编程， 从iPSC产生人神经元、星形胶质细胞和小胶质细胞的纯化培养物， 遗传背景或预期易感性。因为APOE的变异对AD风险和 我们将分析来自每种APOE基因型的同基因iPSC的EV的EV货物（EV cargo）， 使用最先进的蛋白质组学和RNA测序方法。与此同时，我们将解决功能性后果 EV对人类诱导神经元的生物活性的两个敏感读数：成像神经元连接和 突触动力学和无偏转录组学分析。这些合作研究将建立一个新的 EV货物多样性和信号传导生物活性的基于细胞类型的概况的目录。比较EV内容， 病理风险和保护性变体有可能揭示与细胞间相互作用相关的新机制。 传播致病性或保护性信号，并鉴定候选生物标志物以在人类临床样品中进行测试 AD患者。