Origins, properties, and therapeutic potential of cells that repopulate the microglia-depleted adult brain

重新填充小胶质细胞耗尽的成人大脑的细胞的起源、特性和治疗潜力

• 批准号: 10335278
• 负责人: Kim Green
• 金额: $ 37.35万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335278
• 关键词: Actins; Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Appearance; Astrocytes; Axon; Back; Behavior; Brain; Brain Diseases; Cells; Clinical; Clinical Trials; Cognition; Cytoskeleton; Dendritic Spines; Development; Disease; Disease Progression; Endothelial Cells; Gene Expression; Gene Expression Profile; Health; Homeostasis; Inflammation; Injury; Long-Term Potentiation; Macrophage Colony-Stimulating Factor Receptor; Microglia; Modeling; Morphology; Mus; Myelogenous; Myeloid Cells; Neurons; Nucleosomes; Oligodendroglia; Pathology; Pericytes; Phagocytes; Phenotype; Proliferating; Property; Recovery of Function; Reporting; Route; Signal Transduction; Source; Stains; Stream; Synapses; Synaptic plasticity; Therapeutic; Time; Tissues; Withdrawal; Work; aging brain; brain cell; cell type; density; drug withdrawal; functional outcomes; improved; inhibitor; juvenile animal; macrophage; mouse model; neurogenesis; neuroinflammation; novel; postnatal development; response; restoration; transcriptome; transcriptome sequencing; white matter

Abstract: We discovered microglia in the adult brain are dependent on signaling through the colony-stimulating factor 1 receptor (CSF1R), and identified several CSF1R inhibitors that crossed into the brain, leading to the elimination of most of the microglia. This remarkable phenomenon has been widely replicated and is now a standard in the field to explore microglial function in health and disease, and clinical trials are being conducted/planned as a result. We also found that we could eliminate microglia for as long as we continued treatment, but upon drug withdrawal, repopulation of the microglial tissue occurred rapidly from proliferating cells throughout the brain that formed a new microglial tissue in ~14 days. We found we could use this to “reset” the inflamed microglial tissue after injury or in aging, and promote functional recovery/cognition. In this continuation, we seek to understand the source and properties of these repopulating cells that become microglia, and study how they modulate neuronal gene expression to rejuvenate the aged brain and fully restore long-term potentiation to that of a young animal. In addition, we describe a second slower source of microglial repopulation, that originates in specific brain niches – the rostral migratory stream (RMS) and associated projecting axonal tracts. This “alternative” repopulation is only unmasked by the complete elimination of microglia. These “alternative” cells arise from unknown cells within these brain niches, and eventually can break out from the white matter tracts and fill the cortex/brain. These cells never attain the numbers, morphologies, or gene expression of microglia, but resemble microglia found in the RMS, which have pro-neurogenesis and increased phagocytotic capabilities than other microglia. We will determine the source of these “alternative” cells, and the consequences of filling the brain with them, including if they have any therapeutic potential, in a mouse model of Alzheimer's disease.

抽象的： 我们发现成人大脑中的小胶质细胞取决于通过刺激因子1的信号传导 受体（CSF1R），并鉴定 消除大多数小胶质细胞。这种非凡的现象已被广泛复制，现在是 现场探索健康和疾病中小胶质功能的标准，临床试验正在 结果进行/计划。我们还发现，只要我们继续 治疗，但在戒断药物后，小胶质细胞组织的重生迅速发生 整个大脑的细胞在约14天内形成了新的小胶质细胞组织。我们发现我们可以使用它 “重置”受伤或衰老后发炎的小胶质细胞组织，并促进功能恢复/认知。在这个 继续，我们试图了解这些重现的细胞的来源和特性 小胶质细胞，并研究它们如何调节神经元基因表达以使老化的大脑恢复活力并完全 恢复了年轻动物的长期潜力。此外，我们描述了第二个较慢的来源 小胶质细胞的重生，起源于特定的脑壁ches - 延髓迁移流（RMS）和 相关的投射轴突区。这种“替代”重新群仅由完整的 消除小胶质细胞。这些“替代”细胞来自这些脑壁che中未知细胞，以及 最终可以从白质区域爆发，并填充皮质/大脑。这些细胞永远不会达到 小胶质细胞的数量，形态或基因表达，但类似于RMS中的小胶质细胞， 与其他小胶质细胞相比，亲神经发生和增加的吞噬能力。我们将确定来源 这些“替代”细胞以及用它们充满大脑的后果，包括它们是否有任何 在阿尔茨海默氏病小鼠模型中的治疗潜力。