Identifying signatures of brain aging through heterochronic blood exchange

项目摘要 生活水平的提高和现代医学的进步极大地延长了人类的生命 预期寿命。然而，与衰老相关的功能衰退和疾病，特别是认知障碍和 神经退行性变也变得更加普遍。异时血液交换的研究表明 衰老的全身环境抑制幼年动物的神经发生并损害认知功能，提示 存在有损大脑健康的增龄系统性因素。特别是，炎症可能会成为 过度和慢性的衰老(“发炎”)，损害正常的大脑功能。因此，蛋白质参与了 炎症反应，如细胞因子，是与大脑老化有关的这些系统性因素的候选因素。 根据已发表的文献和我们最近的发现，我们假设与衰老相关的改变在 全身炎症因子激活小胶质细胞(中枢神经系统中的常驻免疫细胞)和 导致小胶质细胞介导的突触丢失；恢复这些因子在健康年轻人中的表达模式 国家挽救了突触缺陷，改善了认知功能。在目标1中，我们将使用生物正交非 典型氨基酸标记(BONCAT)确定如何使用Alk5抑制剂(Alk5i)的鸡尾酒治疗 催产素(OT，一种神经营养、抗炎多肽)或异慢性血液交换会影响 炎症相关全身因子在脑及外周组织中的表达及分布。 目的2研究Alk5i OT治疗和异慢性血液交换如何影响神经免疫相互作用 在大脑中，利用体内双光子成像来研究小胶质细胞-突触的相互作用及其 对大脑皮层突触完整性和动力学的影响。使用阵列层析成像，一种高通量、超级 分辨率蛋白质组成像技术，Aim 3进行大分子的分子解剖和重建 个体突触的群体，并决定Alk5I OT治疗和异时血液的效果 突触分子信号交换和炎性细胞因子在脑内的分布。加在一起，这些 研究将提供血液对大脑蛋白质组特定年龄影响的综合特征。 和突触回路，以及概述负责脑老化的候选机制(S)。

Project Summary The improvement in living standards and the advancement in modern medicine have greatly extended human life expectancy. However, aging-related functional decline and diseases, in particular cognitive impairment and neurodegeneration, also become more prevalent. Studies of heterochronic blood exchange reveal that the aged systemic milieu inhibits neurogenesis and impairs cognitive functions in young animals, suggesting the existence of age-elevated systemic factors detrimental to brain health. In particular, inflammation may become excessive and chronic with aging (“inflammaging”) and impair normal brain functions. Thus proteins involved in inflammatory responses, such as cytokines, are candidates of such systemic factors implicated in brain aging. Building upon published literature and our recent finding, we hypothesize that aging-associated alterations in systemic inflammatory factors activate microglia (resident immune cells in the central nervous system) and lead to microglia-mediated synapse loss; restoring the expression pattern of such factors to the healthy young state rescues synaptic defects and improves cognitive functions. In Aim 1, we will use bio-orthogonal non- canonical amino acid tagging (BONCAT) to determine how treatment with a cocktail of Alk5 inhibitor (Alk5i) and oxytocin (OT, a neurotrophic, anti-inflammatory peptide) or heterochronic blood exchange affects the expression profile and distribution of inflammaging-related systemic factors in the brain and peripheral tissues. Aim 2 examines how Alk5i+OT treatment and heterochronic blood exchange affect neuro-immune interaction in the brain, taking advantage of in vivo two-photon imaging to study microglia-synaptic interactions and their effects on synaptic integrity and dynamics in the cortex. Using Array Tomography, a high-throughput, super- resolution proteomic imaging technique, Aim 3 conducts molecular dissection and reconstruction of large populations of individual synapses and determines the effect of Alk5i+OT treatment and heterochronic blood exchange on synaptic molecular signatures and inflammatory cytokine distribution in the brain. Together, these studies will provide a comprehensive characterization of age-specific effects of blood on the brain proteome and synaptic circuits, and outline candidate mechanism(s) responsible for brain aging.