Systemic Mechanisms of Brain Rejuvenation

大脑年轻化的系统机制

• 批准号: 10634570
• 负责人: SAUL A VILLEDA
• 金额: $ 54.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634570
• 关键词: Adult; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Animals; Attenuated; Biological Assay; Blood; Blood - brain barrier anatomy; Blood Platelets; Brain; Cardiovascular system; Cells; Circulation; Coagulation Process; Cognition; Cognitive; Data; Dementia; Disease; Elderly; Exercise; Exposure to; Hippocampus; Human; Immune; Impaired cognition; Impairment; In Vitro; Incidence; Learning; Mass Spectrum Analysis; Mediating; Memory; Microglia; Molecular; Mus; Neurodegenerative Disorders; PF4 Gene; Parabiosis; Pathway interactions; Peripheral; Plasma; Population; Proteomics; Regenerative capacity; Regulation; Rejuvenation; Research; Role; Testing; Therapeutic; Therapeutic Effect; adult neurogenesis; age related; age related neurodegeneration; age related neuroinflammation; aged; aging brain; aging hippocampus; behavior test; chemokine; cognitive benefits; cognitive function; glial activation; immunoregulation; improved; in vivo; insight; memory process; mouse model; neurodegenerative phenotype; neurogenesis; neuroinflammation; new therapeutic target; novel therapeutics; programs; regenerative; single-cell RNA sequencing; systemic intervention; theories; therapeutic candidate; therapeutic target; trafficking; translational potential

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.

项目总结/摘要 通过靶向系统环境中的循环因子来增强认知的能力提供了独特的和有效的治疗方法。 未被充分探索的大脑老化治疗方法。我们和其他人已经证明，系统性的操纵， 包括通过异时共生（其中年轻人的循环系统 和老年动物加入）和年轻血浆给药，使老年海马恢复活力， 改善老年小鼠的认知能力下降。年轻血液的返老还童效果反映了那些观察到的 运动，假定共同的血源性作用机制，广泛的系统性干预措施发挥其作用， 有益效果。我们实验室的初步数据表明，全身给予血小板因子 从幼稚的年轻小鼠或运动的小鼠逆转成年神经发生中与年龄相关的损伤， 减少神经炎症并恢复老年小鼠的认知功能。此外，使用蛋白质组学，我们的两个 研究小组已经独立鉴定了CXCL 4/血小板因子4（PF 4）--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-作为一种潜在的年轻血液来源， 运动诱导的抗衰老循环因子。这项拟议的研究将探讨恢复活力和 血小板因子对脑老化的治疗作用具体来说，我们的假设是，系统性暴露于 血小板因子使成人神经发生恢复活力，减轻神经炎症并改善认知， 改善神经退行性表型。我们将测试这个理论有三个具体目标：1：确定 PF 4下游机制是老年海马体认知和再生再生的基础。 2：检查PF 4对老年海马神经炎症的恢复作用。3：调查 PF 4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，将血小板衍生的循环因子鉴定为候选治疗因子， 目标是恢复年龄相关的认知功能障碍，并可能治疗痴呆相关的神经退行性疾病， 老年痴呆症等疾病。