Regulation of microglial function by blood-borne factors

血源性因子对小胶质细胞功能的调节

• 批准号: 10679408
• 负责人: Brittany Marie Hemmer
• 金额: $ 4.61万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679408
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Animals; Blood; Brain; Cells; Central Nervous System; Chronic; Communication; Confocal Microscopy; Data; Dendritic Spines; Development; Disease; Disease Marker; Disease Progression; Disease associated microglia; Environment; Exhibits; Exposure to; Extracellular Matrix; Extracellular Protein; Extracellular Space; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Hippocampus; Homeostasis; Human; Inflammation; Inflammatory; Inflammatory Response; Injury; Intercellular Fluid; Long-Term Potentiation; Macrophage; Maintenance; Matrix Metalloproteinases; Mediating; Memory; Metabolism; Methods; Microdialysis; Microglia; Modeling; Molecular; Morphology; Mus; Myeloid Cells; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neuroimmune; Neurons; Organ; Pathologic; Pathology; Phagocytosis; Phenotype; Plasma; Play; Process; Proteins; Regulation; Rejuvenation; Resolution; Risk Factors; Role; Saline; Surveys; Synapses; Synaptic plasticity; Testing; Therapeutic; Thromboplastin; Tissue Inhibitor of Metalloproteinases; Tissues; Wild Type Mouse; Work; Youth; age related; aged; aging brain; aging population; amyloid pathology; cellular targeting; cognitive change; cognitive performance; confocal imaging; cytokine; effective therapy; experience; experimental study; extracellular; glial activation; improved; in vivo; innovation; insight; mouse model; nervous system disorder; novel strategies; response; restoration; senescence; superresolution microscopy; targeted treatment; therapy development; transcriptome sequencing; wasting

Project Summary: Age-related disorders such as Alzheimer’s disease (AD) present urgent issues to the aging population. Given the lack of universally effective treatments, novel approaches must be developed to reduce the impact of aging, the greatest risk factor for development of AD. Recent work has shown rejuvenation of age- sensitive organs, including the brain, through exposure to young blood. Our lab identified a loss of tissue inhibitor of metalloproteinase 2 (TIMP2) expression with age, and its restoration is critical in mediating the rejuvenating effects of young blood in aged animals. Despite these findings, the precise mechanism and cellular targets of TIMP2 have yet to be identified. It is currently unknown whether the positive effects of TIMP2 in aging generalize to the context of AD pathology. However, aging and AD present similar environmental challenges to the brain (e.g., inflammation, cellular debris from dying cells, toxic proteins). Based on the role of microglia in rapidly responding to debris (e.g., dying cells, amyloid, etc), we hypothesize that TIMP2 modulates microglial function. Consistent with this hypothesis, we have found that treatment with TIMP2 reduces microglial activation in the aged brain. Upon exposure to the debris of aging and AD, a subset of microglia acquires a disease- associated microglia (DAM) phenotype to respond to these challenges. This phenotype is initially protective by allowing microglia to effectively respond to environmental challenges, but unbridled activation can cause dysfunction or senescence of microglia and damage to surrounding tissue. Restoration of an effective response to debris may be critical to limit pathology. TIMP2 has been found to be a marker of the DAM transcriptional profile, and our preliminary data indicate that cell-intrinsic TIMP2 can regulate microglial state. This proposal aims to characterize microglial response to TIMP2 treatment and the cell-intrinsic role of microglial TIMP2 in enabling an effective response to debris in differing pathological contexts. Aim 1 will assess the morphological and inflammatory responses of microglia following treatment with TIMP2 in aged and AD pathological contexts to determine how microglia respond to damage following treatment. Furthermore, we will examine microglial- neuronal interactions in hippocampus using super-resolution microscopy and RNAscope. To probe the cell- intrinsic role of microglial TIMP2, Aim 2 will test the hypothesis that microglial TIMP2 rejuvenates response to aging and AD-associated pathology. We developed a mouse model that allows us to conditionally delete TIMP2 within microglia in diverse contexts. Upon deletion, we will examine response to debris by analyzing changes in pathology, morphology, cytokine release, and microglia-neuron interactions. The innovative methods employed in this proposal will provide insights into the role of TIMP2 acting as an extracellular protein on the function of microglia, while also probing cell-intrinsic effects of its activity in the context of debris associated with aging and AD. Characterization of the neuroimmune response to debris in different pathological conditions may facilitate development of therapies that slow down the aging process to limit onset of neurodegenerative diseases.

项目概述：阿尔茨海默病（AD）等与阿尔茨海默病相关的疾病是老年人面临的紧迫问题 人口由于缺乏普遍有效的治疗方法，必须开发新的方法来减少 衰老的影响是AD发展的最大风险因素。最近的研究表明年轻化- 敏感器官，包括大脑，通过接触年轻的血液。我们的实验室发现 金属蛋白酶抑制剂2（TIMP 2）的表达与年龄有关，其恢复在介导 年轻血液对老年动物的恢复活力作用。尽管有这些发现， TIMP 2的靶点尚未确定。目前尚不清楚TIMP 2在衰老中的积极作用是否 概括到AD病理学的背景。然而，老化和AD对人类提出了类似的环境挑战， 大脑（例如，炎症、垂死细胞的细胞碎片、有毒蛋白质）。基于小胶质细胞在 快速响应碎片（例如，死亡细胞，淀粉样蛋白等），我们假设TIMP 2调节小胶质细胞 功能与这一假设相一致，我们发现用TIMP 2治疗可以减少小胶质细胞的活化， 在老年人的大脑中。当暴露于老化和AD的碎片时，小胶质细胞的一个子集获得疾病- 相关的小胶质细胞（DAM）表型来应对这些挑战。这种表型最初是由 使小胶质细胞能够有效应对环境挑战，但不受约束的激活可能会导致 小胶质细胞的功能障碍或衰老以及对周围组织的损伤。恢复有效对策 可能是限制病理学的关键。TIMP 2已被发现是DAM转录的标志物， 我们的初步数据表明，细胞内源性TIMP 2可以调节小胶质细胞状态。这项建议 目的是表征小胶质细胞对TIMP 2治疗的反应以及小胶质细胞TIMP 2在小胶质细胞中的细胞内在作用。 从而能够在不同的病理情况下对碎片做出有效的反应。目标1将评估形态学 在老年和AD病理背景下用TIMP 2治疗后小胶质细胞的炎症反应 以确定小胶质细胞在治疗后对损伤的反应。此外，我们将检查小胶质细胞- 海马神经元的相互作用，使用超分辨率显微镜和RNAscope。探测细胞- 小胶质细胞TIMP 2的内在作用，目标2将测试小胶质细胞TIMP 2恢复对 衰老和AD相关病理学。我们开发了一种小鼠模型，使我们能够有条件地删除TIMP 2 在不同的环境中的小胶质细胞。删除后，我们将通过分析 病理学、形态学、细胞因子释放和小胶质细胞-神经元相互作用。采用的创新方法 在这项建议将提供深入了解TIMP 2作为细胞外蛋白的作用， 小胶质细胞，同时也探测其活性在与衰老相关的碎片背景下的细胞内在效应， AD.在不同的病理条件下，对碎片的神经免疫反应的表征可能有助于 开发减缓衰老过程的疗法，以限制神经退行性疾病的发作。