Development of a microbial-rich exposure regimen to accelerate translational research using mouse models of Alzheimer's Disease to humans.

开发富含微生物的暴露方案，以加速使用阿尔茨海默病小鼠模型对人类的转化研究。

• 批准号: 10681908
• 负责人: Gregorio Valdez
• 金额: $ 19.94万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681908
• 关键词: Acceleration; Adult; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapy; Amyloid; Amyloidosis; Animal Model; Animals; Antigens; Basic Science; Brain; Brain Stem; Brain region; CD8B1 gene; Cell Maturation; Cells; Cessation of life; Data; Development; Disease; Environment; Exposure to; Failure; Female; Flow Cytometry; Future; Genetic; Genetic Transcription; Gliosis; Hippocampus; Human; Immune; Immune response; Immune system; Immunohistochemistry; Impaired cognition; Incidence; Infiltration; Laboratories; Liver; Lymphoid; Lymphoid Tissue; Masks; Medial; Microbe; Microglia; Modeling; Molecular; Mus; Neurodegenerative Disorders; Organ; Pathogenesis; Pathologic; Pathway interactions; Peripheral; Phenotype; Play; Population; Prefrontal Cortex; Publishing; Regimen; Regulatory T-Lymphocyte; Reporting; Reproducibility; Research; Research Personnel; Rodent; Role; Senile Plaques; Spleen; Stains; Synapses; T cell differentiation; Tauopathies; Testing; Tissues; Translating; Translational Research; Visualization; Work; amyloid pathology; cognitive function; commensal microbes; defined contribution; design; effective therapy; experimental study; fighting; germ free condition; human disease; human model; indexing; insight; lymph nodes; male; microbial; monocyte; mouse model; neuron loss; neuropathology; novel; novel strategies; pathogen; pathogenic microbe; prevent; residence; tau Proteins; trafficking; trait; transmission process; trend

Project Summary Accumulating evidence over the years suggests that microbial exposure and the ensuing immune response has a large role in the incidence and progression of age-associated neurodegenerative diseases, including in Alzheimer’s Disease (AD). Yet, research on this neurodegenerative disease has primarily utilized genetic mouse models that are reared in ultra-hygienic specific pathogen free (SPF) laboratory environments. The highly sanitized SPF environment prevents inadvertent microbial exposure and reduces experimental variability. But without routine microbial stimulation, the immune system of these SPF mice remains in a predominantly naïve state comprising mostly of antigen-inexperienced immune cell populations. Importantly, these naïve cells remain sequestered in the lymphoid tissues and do not access disease-affected organs. Thus, studying animals reared in SPF conditions may mask important contributions of the immune system to neurodegenerative diseases. If true, this may be a major contributing factor to the failure of translating findings from rodents to humans, which are naturally exposed to a variety of pathogens. Dr. Beura (co-investigator in this application) has demonstrated that SPF mice co-housed with pet store mice (herein referred as “dirty” mice) not only have a higher number of immune cells in peripheral organs, as compared to SPF mice, but their immune cells also display maturation traits that are more typical of the human immune system. Based on these findings and the known role of the immune system in AD, we assessed the impact of a pathogen-rich environment on the 5XFAD mouse model of AD. We present preliminary data demonstrating that the immune system is heightened in dirty compared to SPF 5XFAD mice. Additionally, our preliminary data show increased gliosis in 6-month-old dirty compared to SPF 5XFAD mice. While these findings are promising, cohousing approaches have several shortcomings that limit its wider deployment, including variable transmission of pathogens and fighting among male mice. To overcome these limitations, we developed a new microbial exposure regimen that optimizes pathogen transmission leading to reproducible changes in the immune system of both male and female mice. In this proposal, we will use this novel regimen to define the contribution of a pathogen-rich environment and matured plus heightened immune system on AD mouse models of amyloid pathology. To establish this novel approach, we will perform experiments in two aims. First, we will determine the impact of a pathogen-rich environment on immune maturation in two mouse models of AD amyloid neuropathology, 5XFAD and APPNL-F, and a mouse model of AD tauopathy, PS19. Second, we will determine the timing and magnitude of AD pathological indices in 5XFAD, APPNL-F and PS19 mice exposed to dirty and SPF conditions. Together, the proposed experiments will provide unique insights about the underpinning of AD pathogenesis and reveal unique contributions of a microbe-rich environment and matured immune system.

项目摘要 多年来积累的证据表明，微生物的暴露和随之而来的免疫响应具有 在与年龄相关的神经退行性疾病的事件和进展中起着重要作用，包括 阿尔茨海默氏病（AD）。然而，对这种神经退行性疾病的研究主要利用了遗传小鼠 在超绿色特异性病原体（SPF）实验室环境中饲养的模型。高度 消毒的SPF环境可防止无意间的微生物暴露并降低实验变异性。 如果没有常规的微生物刺激，这些SPF小鼠的免疫系统仍处于主要天真状态 状态主要完成抗原 - 抗原的免疫细胞群体。重要的是，这些幼稚的细胞仍然存在 在淋巴组织中隔离，不进入受疾病影响的器官。那是研究动物饲养的 在SPF条件下，可以掩盖免疫系统对神经退行性疾病的重要贡献。如果 没错，这可能是将发现从啮齿动物转化为人类的失败的主要因素， 自然暴露于各种病原体。 Beura博士（本应用程序中的共同研究器）已证明 那个与宠物店小鼠共同居住的SPF小鼠（此处称为“脏”小鼠）不仅具有较高的数量 与SPF小鼠相比，外围器官中的免疫细胞，但其免疫细胞也显示成熟 人类免疫系统更典型的特征。基于这些发现和已知的作用 AD中的免疫系统，我们评估了富含病原体环境对5xFAD小鼠模型的影响 广告。我们提供了初步数据，表明与SPF相比，免疫系统在肮脏中加剧了 5xfad小鼠。此外，我们的初步数据表明，与SPF相比，6个月大的脏神经病增加 5xfad小鼠。尽管这些发现是有希望的，但同居的方法有几个缺点，以限制其 广泛的部署，包括病原体的可变传播和雄性小鼠的战斗。克服 这些局限性，我们开发了一种新的微生物暴露方案，该方案优化了病原体传播领先 重现雄性和雌性小鼠免疫系统的变化。在此提案中，我们将使用此 新的疗法，以定义富含病原体环境和成熟加强免疫力的贡献 淀粉样病理的AD小鼠模型上的系统。为了建立这种新颖的方法，我们将执行 实验有两个目标。首先，我们将确定富含病原体环境对免疫的影响 AD淀粉样神经病理学，5XFAD和APPNL-F的两个小鼠模型的成熟，以及AD的小鼠模型 Tauopathy，PS19。其次，我们将确定5xfad中AD病理指数的时间和幅度， AppNL-F和PS19小鼠暴露于肮脏和SPF条件下。拟议的实验将共同提供 关于AD发病机理的基础的独特见解，并揭示了富含微生物的独特贡献 环境和成熟的免疫系统。