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.

项目概要 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已经 在与年龄相关的神经退行性疾病的发生和进展中发挥着重要作用，包括 然而，对这种神经退行性疾病的研究主要利用基因小鼠。 在超卫生的无特定病原体 (SPF) 实验室环境中饲养的模型。 消毒后的 SPF 环境可防止无意的微生物暴露并减少实验变异性。 在没有常规微生物刺激的情况下，这些 SPF 小鼠的免疫系统仍处于初始状态 重要的是，这些初始细胞仍然存在。 隔离在淋巴组织中并且不接触受疾病影响的器官因此，研究饲养的动物。 在 SPF 条件下，可能会掩盖免疫系统对神经退行性疾病的重要贡献。 确实，这可能是将啮齿类动物的发现转化为人类的失败的一个主要因素。 Beura 博士（本申请的共同研究员）已经证明，它们自然会暴露于多种病原体。 与宠物店小鼠（本文称为“脏”小鼠）共同饲养的 SPF 小鼠不仅具有更高的 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表现出成熟 基于这些发现和已知的作用，人类免疫系统具有更典型的特征。 为了研究 AD 中的免疫系统，我们评估了富含病原体的环境对 5XFAD 小鼠模型的影响 AD 我们提供的初步数据表明，与 SPF 相比，脏污中的免疫系统令人惊叹。 此外，我们的初步数据显示，与 SPF 小鼠相比，6 个月大的 dirty 小鼠的神经胶质细胞增生有所增加。 虽然这些发现很有希望，但 5XFAD 小鼠的共养方法有一些缺点限制了其应用。 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。 针对这些限制，我们开发了一种新的微生物暴露方案，可优化病原体传播 在雄性和雌性小鼠的免疫系统中产生可重复的变化，在本提案中，我们将使用它。 新的方案来定义富含病原体的环境和成熟的抗生素的贡献 为了建立这种新方法，我们将进行 AD 小鼠淀粉样蛋白病理学系统的研究。 首先，我们将确定富含病原体的环境对免疫的影响。 两种 AD 淀粉样蛋白神经病理学小鼠模型（5XFAD 和 APPNL-F）以及 AD 小鼠模型的成熟 tau蛋白病，PS19 其次，我们将确定5XFAD中AD病理指标的时间和程度， APPNL-F 和 PS19 小鼠暴露于肮脏和 SPF 条件下，拟议的实验将提供。 关于 AD 发病机制的独特见解，并揭示了富含微生物的独特贡献 环境和成熟的免疫系统。