Systemic Mechanisms of Brain Rejuvenation

项目摘要/摘要 通过瞄准系统环境中的循环因素来增强认知的能力提供了一种独特的 对大脑老化的治疗方法探索不足。我们和其他人已经证明了系统性的操纵， 包括通过异慢性异种共生暴露在年轻血液中(在这种情况下，年轻人的循环系统 和老年动物联合)和青年血浆给药，重振老年海马体和 改善衰老小鼠的认知功能减退。年轻血镜的返老还童效果观察 运动，假定广泛的系统性干预通过共同的血液传播的行动机制发挥其 有益的影响。来自我们实验室的初步数据表明，系统性给药的血小板因子源于 无论是幼龄小鼠还是运动小鼠，都能逆转成年神经发生中与年龄相关的损伤， 减轻神经炎症，恢复老龄小鼠的认知功能。此外，利用蛋白质组学，我们的两个 研究小组已经独立确定了CXCL4/血小板因子4(PF4)--一种从血小板释放的趋化因子， 参与凝血和各种免疫调节功能-作为潜在的年轻血液来源和 运动性抗老年循环因子。拟议的研究将调查年轻化和 血小板因子对老年脑的治疗作用。具体地说，我们的假设是系统性暴露于 血小板因子使成人神经再生恢复活力，减轻神经炎症，改善认知，而 改善神经退行性变表型。我们将以三个具体目标来检验这一理论：1：确定 PF4下游机制在老年海马区认知和再生再生中的潜在作用。 2：观察PF4对老龄大鼠海马神经炎症的返老性作用。3：调查 PF4在阿尔茨海默病小鼠模型中的有益作用。成功完成这些研究将 具有显著的翻译潜力，确定血小板衍生循环因子作为候选治疗因素 恢复年龄相关性认知功能障碍和潜在治疗痴呆症相关神经退行性变的目标 阿尔茨海默氏症等疾病。

PROJECT SUMMARY/ABSTRACT The ability to enhance cognition by targeting circulating factors in the systemic milieu provides a unique and underexplored therapeutic approach to brain aging. We and others have shown that systemic manipulations, including exposure to young blood through heterochronic parabiosis (in which the circulatory system of a young and old animal are joined) and young blood plasma administration, revitalize the aged hippocampus and ameliorate cognitive decline in aged mice. The rejuvenating effects of young blood mirror those observed with exercise, positing common bloodborne mechanisms of action by which broad systemic interventions exert their beneficial effects. Preliminary data from our labs indicate that systemic administration of platelet factors derived from either naïve young mice or exercised mice reverses age-related impairments in adult neurogenesis, deceases neuroinflammation and restores cognitive function in aged mice. Moreover, using proteomics, our two groups have independently identified CXCL4/platelet factor 4 (PF4)—a chemokine released from platelets, involved in coagulation and a variety of immunomodulatory functions—as a potential young blood-derived and exercise-induced anti-geronic circulating factor. The proposed study will investigate the rejuvenating and therapeutic effects of platelet factors on the aged brain. Specifically, our hypothesis is that systemic exposure to platelet factors rejuvenates adult neurogenesis, attenuates neuroinflammation and improves cognition, while ameliorating neurodegenerative phenotypes. We will test this theory with three specific aims: 1: Determine mechanisms downstream of PF4 underlying cognitive and regenerative rejuvenation in the aged hippocampus. 2: Examine the rejuvenating effects of PF4 on neuroinflammation in the aged hippocampus. 3: Investigate the beneficial effects of PF4 in a mouse model of Alzheimer’s disease. Successful completion of these studies will have significant translational potential, identifying platelet-derived circulating factors as candidate therapeutic targets to restore age-related cognitive dysfunction and potentially treat dementia-related neurodegenerative disorders such as Alzheimer’s disease.