TYROBP/DAP12: a hub protein linking Alzheimer's disease, microglia, and gut microbiome.

TYROBP/DAP12：一种连接阿尔茨海默病、小胶质细胞和肠道微生物组的中心蛋白。

• 批准号: 10303358
• 负责人: Jean-Vianney Haure-Mirande
• 金额: $ 16.92万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303358
• 关键词: 16S ribosomal RNA sequencing; 3xTg-AD mouse; APP-PS1; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Antibiotics; Appearance; Behavioral; Biochemical; Brain; Characteristics; Clinical; Cognitive deficits; Complement 1q; Data; Development; Disease; Disease Progression; Electrophysiology (science); Extravasation; Fluorescence; Gas Chromatography; Genes; Genomic approach; Goals; Housing; Human; Immune; Inflammation; Intervention; Intestinal permeability; Knockout Mice; Link; Measures; Medicine; Messenger RNA; Microglia; Molecular; Morphology; Mus; Mutation; Oral; Outcome Study; Pathogenesis; Pathologic; Pathway Analysis; Pathway interactions; Physiological; Physiology; Play; Population; Prophylactic treatment; Proteins; Regulation; Reporting; Research; Rodent; Role; Senile Plaques; Serum; Severity of illness; Signal Transduction; Specific qualifier value; TREM2 gene; TYROBP gene; Testing; Therapeutic; Therapeutic Intervention; Volatile Fatty Acids; abeta accumulation; abeta deposition; aged; amyloid pathology; cerebral amyloidosis; disease phenotype; fecal microbiota; fluorescein isothiocyanate dextran; gene induction; genetic approach; gut bacteria; gut microbiome; gut microbiota; gut-brain axis; insight; learned behavior; link protein; medical schools; microbiota; microbiota-gut-brain axis; mouse model; novel; novel strategies; object recognition; polypeptide; prevent; programs; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; young adult

ABSTRACT Recent genetic and genomic approaches have converged on the role of microglia and inflammation in the pathogenesis of Alzheimer’s disease (AD), potentially presenting novel opportunities for developing prophylaxis and/or therapeutics against AD. In a multiscale gene network analysis, a group at the Icahn School of Medicine at Mount Sinai highlighted TYROBP (aka DAP12) as a key driver gene in microglia activation and AD pathogenesis. TYROBP is one of the first “hits” to emerge from the integrative multi-scale approach to sporadic AD that forms the basis for the AMP-AD Accelerating Medicines Partnership in AD) Program. Our previous studies in the APP/PS1 mouse model of AD pathology suggest that reduction of TYROBP at the mRNA or protein level or inhibition of its activity could represent a potential therapeutic target for AD prevention or treatment by repressing the expression of C1q and the induction of genes involved in the switch from homeostatic microglia to disease-associated microglia. Gut microbiota have also been advanced as a modulator of microglial activity and amyloid pathology. The overall goal of this study is to elucidate the role of TYROBP, the gut microbiota, and their interaction on the regulation of brain physiology and AD. We propose two complementary aims. First, we will identify the role and interaction of TYROBP and the gut microbiota on the regulation of the brain transcriptome during physiological aging or during the onset and progression of amyloid pathology. We will perform RNA sequencing and compare the transcriptomic profiles of WT and APP/PS1 mice that are, respectively either WT or KO at the Tyrobp locus and that harbor either (a) normal gut flora in normal abundance, (b) normal gut flora in reduced abundance or (c) pathological gut microbiota mimicking the flora identified in mouse AD gut. Using 16S rRNA sequencing, we will identify changes in bacterial populations due to gut microbiota-related maneuvers and modulation of TYROBP levels and will attempt to establish a causal link between gut microbiota and the immune-Tyrobp regulated transcriptome. Second, we will define how TYROBP level interacts with the gut microbiota, and how, in turn, these variables modulate AD phenotype and microglia activation. We will perform a panel of behavioral and biochemical analyses in order to determine whether modulation of levels and/or types of gut microbiota, TYROBP expression levels, or the combination of both result in changes in microglial activity and AD pathogenesis. The expected outcome of this study is to generate important novel experimental results that will elucidate the role and the mechanisms of microbiota regulation of microglia activation and AD. This project will also generate important data to determine whether the modulation of different types, levels, and ratios of gut bacteria could modulate TYROBP activity and form the basis for clinical interventions aimed at slowing or preventing AD.

抽象的 最近的遗传学和基因组方法集中在小胶质细胞和炎症在炎症中的作用上。 阿尔茨海默病（AD）的发病机制，可能为开发预防措施提供新的机会 和/或针对 AD 的治疗。在多尺度基因网络分析中，伊坎医学院的一个小组 西奈山强调 TYROBP（又名 DAP12）是小胶质细胞激活和 AD 的关键驱动基因 发病。 TYROBP 是通过综合多尺度方法解决零星问题的首批“热门产品”之一。 AD 构成了 AMP-AD 加速药物合作伙伴关系 (AD) 计划的基础。我们之前的 AD 病理学 APP/PS1 小鼠模型的研究表明，mRNA 或蛋白质上的 TYROBP 减少 其活性的水平或抑制可能代表 AD 预防或治疗的潜在治疗靶点 抑制 C1q 的表达并诱导参与小胶质细胞稳态转换的基因 与疾病相关的小胶质细胞。肠道微生物群也已被发展为小胶质细胞活性的调节剂 和淀粉样蛋白病理学。本研究的总体目标是阐明 TYROBP（肠道 微生物群及其对大脑生理学和 AD 调节的相互作用。我们建议两个 互补的目标。首先，我们将确定 TYROBP 和肠道菌群对肠道菌群的作用和相互作用。 生理衰老或淀粉样蛋白发生和进展过程中大脑转录组的调节 病理。我们将进行 RNA 测序并比较 WT 和 APP/PS1 小鼠的转录组图谱 Tyrobp 基因座分别为 WT 或 KO，并且在正常情况下具有 (a) 正常肠道菌群 丰度，(b) 丰度降低的正常肠道菌群或 (c) 模仿菌群的病理肠道微生物群 在小鼠 AD 肠道中发现。使用 16S rRNA 测序，我们将识别由于以下原因导致的细菌种群变化 肠道微生物群相关的操作和 TYROBP 水平的调节，并将尝试建立因果关系 肠道微生物群与免疫 Tyrobp 调节的转录组之间的联系。其次，我们将定义如何 TYROBP 水平与肠道微生物群相互作用，以及这些变量如何调节 AD 表型和 小胶质细胞激活。我们将进行一组行为和生化分析，以确定 无论是调节肠道微生物群的水平和/或类型、TYROBP 表达水平，还是以下因素的组合 两者都会导致小胶质细胞活性和 AD 发病机制的变化。 这项研究的预期结果是产生重要的新颖实验结果，以阐明 微生物群调节小胶质细胞激活和 AD 的作用和机制。该项目还将产生 确定不同类型、水平和比例的肠道细菌的调节是否可以发挥作用的重要数据 调节 TYROBP 活性并构成旨在减缓或预防 AD 的临床干预措施的基础。