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: 10468998
• 负责人: Jean-Vianney Haure-Mirande
• 金额: $ 16.9万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468998
• 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 Progression; Disease associated microglia; 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; gene network; 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.

摘要 最近的遗传学和基因组学方法已经集中在小胶质细胞和炎症在肿瘤发生中的作用。 阿尔茨海默病（AD）的发病机制，可能为开发预防提供新的机会 和/或抗AD的治疗剂。在多尺度基因网络分析中，伊坎医学院的一个小组 在西奈山，TYROBP（又名DAP 12）是小胶质细胞激活和AD的关键驱动基因， 发病机制TYROBP是从综合多尺度方法中出现的第一批“命中”之一， AD是AMP-AD加速AD药物伙伴关系计划的基础。我们以前的 在AD病理学的APP/PS1小鼠模型中的研究表明，TYROBP在mRNA或蛋白水平的降低 其活性的水平或抑制可代表通过以下途径预防或治疗AD的潜在治疗靶点： 抑制C1 q的表达和诱导参与从稳态小胶质细胞转换的基因 疾病相关的小胶质细胞。肠道微生物群也被认为是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的作用， 微生物群，以及它们对脑生理和AD调节的相互作用。我们提出了两 互补的目标。首先，我们将确定TYROBP和肠道微生物群在胃肠道中的作用和相互作用。 在生理老化或淀粉样蛋白的发生和发展过程中对脑转录组的调节 病理我们将进行RNA测序，并比较WT和APP/PS1小鼠的转录组学特征。 即，分别是Tyrobp基因座处的WT或KO，并且具有（a）正常肠道植物群， 丰度，（B）丰度降低的正常肠道植物群，或（c）模拟所述植物群的病理性肠道微生物群 在小鼠AD肠道中鉴定。使用16 S rRNA测序，我们将确定细菌种群的变化， 肠道微生物群相关策略和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。第二，我们将如何定义 TYROBP水平与肠道微生物群相互作用，以及这些变量如何反过来调节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，还是调节 两者都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的实验结果，将阐明 微生物群调节小胶质细胞活化和AD的作用和机制。该项目还将产生 重要的数据，以确定不同类型，水平和比例的肠道细菌的调制是否可以 调节TYROBP活性并形成旨在减缓或预防AD的临床干预的基础。