Mechanisms of youth-associated blood-borne factors regulating CNS rejuvenation

项目摘要/摘要：需要新的方法来对抗与年龄相关的大脑疾病， 包括阿尔茨海默病(AD)。衰老是AD的最大危险因素，但我们缺乏详细的机制 了解正常衰老与阿尔茨海默病的关系。新出现的数据增加了神经可塑性可以 在老化的有机体中恢复活力。这些研究表明，年轻血液中存在的因子具有恢复能力。 对于全身老化的组织，同时暗示系统环境和衰老之间的联系--以及 大脑中与广告相关的变化。通过异种繁殖或通过血浆治疗共享年轻血液的老龄小鼠 注射表现出更好的可塑性和更好的认知能力。我们提供了具体的证据 青年相关蛋白、金属蛋白酶组织抑制因子2和集落刺激因子2 (CSF2)，当系统提供时，重振老龄小鼠的海马体功能。相反，有几个 研究表明，衰老的血液因素驱动关键的衰老表型，包括小胶质细胞增多症和 神经发生，以及海马体依赖的认知缺陷，部分通过CCL11和B2M发挥作用。 这些研究留下了关于系统环境在衰老和衰老中的作用的基本问题 它通过对病理的调节与AD有关。最近的研究支持血液传播因素在 调节大脑的天然免疫细胞--小胶质细胞的状态和功能。鉴于此连接和数据 将许多AD风险基因与先天免疫功能联系起来，有明确的理由来探索衰老之间的联系 小胶质细胞参与AD相关病理改变。在初步研究中，我们发现接触年轻血液 减少老年小鼠大脑中的小胶质细胞增生，提示年轻血液因素调节小胶质细胞的状态 衰老。在这项提案中，我们将严格解决青年相关蛋白在改变小胶质细胞中的作用。 基因表达和形态特征，目的是阐明衰老和阿尔茨海默病之间的联系 病理机制。我们假设与青年相关的因素使老年人的小胶质细胞图谱恢复活力。 大脑和AD病理的背景下。我们将在三个主要目标中解决这一假设：(1)确定 系统性TIMP2对衰老小鼠小胶质细胞基因表达和形态的影响 血源性脑再生在多大程度上受小胶质细胞功能的调节；及(3)评估 TIMP2和CSF2联合系统治疗对年龄相关性和AD相关性改变的影响 小胶质细胞的形态和状态。我们的目标将询问与青年相关的血液传播因素在 使用复杂的方法调节小胶质细胞，以严格定义细胞和病理调节 系统环境，潜在地为AD治疗开发开辟了新的途径。

Project Summary/Abstract: Novel approaches are needed to combat age-associated diseases of the brain, including Alzheimer’s disease (AD). Aging is the strongest risk factor for AD, yet we lack a detailed mechanistic understanding connecting normal aging to AD. Emerging data raise the possibility that neural plasticity can be revitalized in aged organisms. These studies demonstrate that factors present in young blood are restorative for aged tissues throughout the body, while suggesting links between the systemic environment and aging- and AD-related changes in the brain. Aged mice sharing young blood via parabiosis or those treated via plasma injections exhibit improved plasticity and improved cognitive performance. We provided evidence for specific youth-associated proteins, tissue inhibitor of metalloproteinases 2 (TIMP2) and colony-stimulating factor 2 (CSF2), that revitalize hippocampal function in aged mice when provided systemically. Conversely, several studies demonstrate that aged blood factors drive key aging phenotypes, including microgliosis and loss of neurogenesis, as well as hippocampus-dependent cognitive deficits, working in part through CCL11 and B2M. These studies leave fundamental questions open regarding the role of the systemic environment in aging and its link to AD through modulation of pathology. Recent work supports a role of blood-borne factors in modulating the state and function of the brain’s innate immune cells, microglia. Given this connection and data linking many AD risk genes to innate immune function, there is clear rationale to explore the link between aging and AD-related pathology through microglia. In preliminary studies, we find that exposure to young blood reduces microgliosis in the brains of aged mice, suggesting that young blood factors regulate microglia state in aging. In this proposal, we will rigorously address the role of youth-associated proteins in altering microglial gene expression and morphological profiles with the goal of clarifying the link between aging and AD pathomechanisms. We hypothesize that youth-associated factors rejuvenate microglia profiles in the aged brain and in the context of AD pathology. We will address this hypothesis in three major aims: (1) To determine the impact of systemic TIMP2 on microglia gene expression and morphology in aged mice; (2) to characterize the extent to which blood-borne brain rejuvenation is regulated by microglia function; and (3) to evaluate the impact of a combined systemic treatment of TIMP2 and CSF2 on age-associated vs. AD-associated changes in microglia profile and state. Our aims will interrogate the role of youth-associated blood-borne factors in regulating microglia using sophisticated approaches to rigorously define cellular and pathological regulation by the systemic environment, potentially opening novel avenues for AD therapy development.