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.

项目摘要：与年龄相关的疾病，例如阿尔茨海默氏病（AD） 人口。鉴于缺乏普遍有效的治疗，必须开发出新的方法来减少 衰老的影响，是AD开发的最大风险因素。最近的工作显示了年龄的修订 通过暴露于年轻的血液，包括大脑在内的敏感器官。我们的实验室确定了组织的损失 金属蛋白酶2（TIMP2）表达的抑制剂随着年龄的增长至关重要，对于介导 年轻动物中年轻血液的振兴作用。尽管有这些发现，精度机制和细胞 TIMP2的目标尚未确定。目前尚不清楚TIMP2在衰老中的积极影响 概括为AD病理的背景。但是，衰老和广告面临类似的环境挑战 大脑（例如炎症，垂死细胞的细胞碎屑，有毒蛋白）。基于小胶质细胞在 我们迅速响应碎屑（例如垂死细胞，淀粉样蛋白等），我们假设TIMP2调节小胶质细胞 功能。与这一假设一致，我们发现用TIMP2治疗减少了小胶质激活 在老化的大脑中。暴露于衰老和AD的碎片后，一部分小胶质细胞会获得疾病 - 相关的小胶质细胞（DAM）表型应对这些挑战。该表型最初受到 允许小胶质细胞有效应对环境挑战，但无限制的激活可能会导致 小胶质细胞的功能障碍或感受和对周围组织的损害。恢复有效响应 对于限制病理可能至关重要。已发现TIMP2是大坝转录的标志 轮廓和我们的初步数据，表明细胞中的TIMP2可以调节小胶质细胞状态。这个建议 旨在表征对TIMP2治疗的小胶质反应和小胶质细胞中TIMP2在 在不同的病理环境下对碎屑产生有效的反应。 AIM 1将评估形态学环境。 在老年和AD病理环境中用TIMP2治疗后小胶质细胞的炎症反应 确定小胶质细胞如何应对治疗后的损害。此外，我们将检查小胶质细胞 使用超分辨率显微镜和rnascope在海马中的神经元相互作用。探测细胞 小胶质timp2的固有作用，AIM 2将检验以下假设：小胶质细胞TIMP2恢复了对的反应 衰老和与广告相关的病理。我们开发了一个鼠标模型，使我们能够有条件删除TIMP2 在潜水员环境中的小胶质细胞中。删除后，我们将通过分析变化来检查对碎屑的反应 使用的创新方法 在此提案中，将提供有关TIMP2作为细胞外蛋白在功能方面的作用的见解 小胶质细胞，同时还探测其活性的细胞中性作用，与衰老和 广告。在不同病理条件下神经免疫性反应对碎屑的表征可能有助于 疗法的发展减慢了衰老过程以限制神经退行性疾病的发作。