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（AD）的特点是突触丧失，导致认知功能下降。 人们越来越认识到 AD 的病理涉及神经元与其他脑细胞类型的相互作用，特别是 小胶质细胞和星形胶质细胞由大脑中的所有细胞分泌，并携带蛋白质和蛋白质。 RNA货物具有从脑组织内的供体细胞向受体细胞发出信号并修改细胞的能力。 功能，如癌症和多种神经系统疾病中病理蛋白的 EV 传播所示。 大脑细胞之间的相互作用是 AD 病理学至少某些方面的一个强有力的候选机制， 表明不同的 EV 货物不仅可以作为疾病的生物标志物，还可以直接诱导 然而，对于电动汽车货物的多样性和对病理疾病状态的脆弱性和保护知之甚少。 与 AD 相关的关键脑细胞类型的生物活性此外，遗传易感性位点或的影响。 其他因素，例如性别，尚未确定 EV 含量、EV 生物活性或变化 为了克服这些障碍，我们建议使用 iPSC 和直接重编程来克服这些障碍。 从 iPSC 中生成人类神经元、星形胶质细胞和小胶质细胞的纯化培养物，这些 iPSC 的 AD 相关性各不相同 因为 APOE 的变异对 AD 风险有很大影响。 (APOE4) 和保护 (APOE2) 我们将分析来自每个 APOE 基因型的同基因 iPSC 的 EV 货物 同时，我们将使用最先进的蛋白质组学和 RNA 测序方法来解决功能后果。 具有两种敏感读数的 EV 对人类诱导神经元的生物活性：成像神经连接和 这些合作研究将建立一种新颖的突触动力学和公正的转录组分析。 基于细胞类型的 EV 货物多样性和信号生物活性的概况目录，比较 EV 内容。 病理风险和保护性变异有可能揭示与细胞间相关的新机制 致病性或保护性信号的传播，并确定候选生物标志物以在人类临床样本中进行测试 AD患者。