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最强的风险因素，但我们缺乏详细的机制， 了解正常衰老与AD之间的联系新出现的数据提高了神经可塑性可以被 在老化的生物体中恢复活力。这些研究表明，存在于年轻血液中的因素是恢复性的， 对于整个身体的老化组织，同时表明系统环境和老化之间的联系-以及 大脑中AD相关的变化。通过联体共生共享年轻血液的老年小鼠或通过血浆处理的老年小鼠 注射显示出改善的可塑性和改善的认知表现。我们提供了证据， 青年相关蛋白、金属蛋白酶组织抑制剂2和集落刺激因子2 （CSF 2），当全身提供时，其在老年小鼠中恢复海马功能。相反，几个 研究表明，衰老的血液因素驱动关键的衰老表型，包括小胶质细胞增生和 神经发生，以及大脑皮层依赖的认知缺陷，部分通过CCL 11和B2 M起作用。 这些研究留下了关于系统环境在衰老中的作用的基本问题， 其通过病理调节与AD联系。最近的研究支持了血液传播因子在 调节大脑先天免疫细胞小胶质细胞的状态和功能。鉴于这种联系和数据 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与 和AD相关的病理通过小胶质细胞。在初步研究中，我们发现接触年轻的血液 减少老年小鼠大脑中的小胶质细胞增生，这表明年轻的血液因子调节老年小鼠大脑中的小胶质细胞状态。 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AD之间的联系 病理机制我们假设，年轻相关因素使老年人的小胶质细胞恢复活力 大脑和AD病理学的背景下。我们将在三个主要目标中解决这个假设：（1）确定 系统性TIMP 2对老年小鼠小胶质细胞基因表达和形态学的影响;（2）表征 通过小胶质细胞功能调节血液传播的脑再生的程度;以及（3）评估 TIMP 2和CSF 2联合全身治疗对年龄相关与AD相关变化的影响 在小胶质细胞的轮廓和状态。我们的目标是询问与青年相关的血液传播因子在 调节小胶质细胞使用复杂的方法来严格定义细胞和病理调节， 全身环境，可能开辟新的途径，AD治疗的发展。

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.