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，微生物暴露和随之而来的免疫反应， 在与年龄相关的神经退行性疾病的发生和进展中起着重要作用， 阿尔茨海默病（AD）。然而，对这种神经退行性疾病的研究主要利用遗传小鼠 在超卫生的无特定病原体（SPF）实验室环境中饲养的模型。高度 经过消毒的SPF环境可防止意外的微生物暴露，并减少实验变异性。但 在没有常规微生物刺激的情况下，这些SPF小鼠的免疫系统仍然处于主要的幼稚状态。 主要由抗原缺乏的免疫细胞群组成的状态。重要的是，这些幼稚细胞 被隔离在淋巴组织中，不能进入受疾病影响的器官。因此，研究饲养的动物 在SPF条件下，可能掩盖免疫系统对神经退行性疾病的重要贡献。如果 的确，这可能是导致研究结果未能从啮齿动物转化为人类的主要因素， 自然地暴露在各种病原体中。Beura博士（本申请的合作研究者）已经证明 与宠物店小鼠（本文中称为“脏”小鼠）共饲养的SPF小鼠不仅具有较高数量的 与SPF小鼠相比，外周器官中的免疫细胞，但它们的免疫细胞也显示成熟 人类免疫系统的典型特征。根据这些发现和已知的作用， 为了研究AD中的免疫系统，我们评估了病原体丰富的环境对5XFAD小鼠模型的影响， AD.我们目前的初步数据表明，免疫系统是提高肮脏相比，SPF 5XFAD小鼠。此外，我们的初步数据显示，与SPF相比， 5XFAD小鼠。虽然这些发现是有希望的，但共居方法有几个缺点，限制了它的应用。 更广泛的部署，包括病原体的可变传播和雄性小鼠之间的战斗。克服 这些限制，我们开发了一种新的微生物暴露方案，优化病原体传播， 雄性和雌性小鼠免疫系统的可重复变化。在本提案中，我们将使用 新的方案，以确定病原体丰富的环境和成熟的贡献加上提高免疫 系统对淀粉样蛋白病理学的AD小鼠模型的影响。为了建立这种新的方法，我们将执行 实验有两个目的。首先，我们将确定病原体丰富的环境对免疫系统的影响。 在两种AD淀粉样蛋白神经病理学小鼠模型5XFAD和APPNL-F以及AD小鼠模型中， tau蛋白病，PS19。其次，我们将确定5XFAD中AD病理指标的时间和幅度， APPNL-F和PS19小鼠暴露于肮脏和SPF条件。总之，拟议的实验将提供 关于AD发病机制基础的独特见解，并揭示了微生物丰富的 环境和成熟的免疫系统。