Exercise-Associated Signaling Against CNS Aging and Alzheimer's Disease

运动相关信号对抗中枢神经系统衰老和阿尔茨海默病

• 批准号: 10589606
• 负责人: Constanza Javiera Cortes
• 金额: --
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10589606
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Automobile Driving; Autophagocytosis; Behavior Therapy; Bioinformatics; Blood Circulation; Brain; Cells; Cognition; Communication; Complement; Computer Models; Data; Data Science; Data Set; Disease; Drug usage; Event; Exercise; FDA approved; Gene Expression Profile; Genetic Transcription; Hippocampus (Brain); Human; Intervention; Machine Learning; Maps; Memory; Metabolic; Metabolism; Modeling; Molecular; Molecular Profiling; Molecular Target; Mus; Muscle; Nerve Degeneration; Nervous System Physiology; Neuraxis; Neurocognitive; Neurodegenerative Disorders; Neurofibrillary Tangles; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Physical Exercise; Physical activity; Physiological; Plasma; Population; Positioning Attribute; Proteins; Proteomics; Risk; Running; Senile Plaques; Signal Transduction; Skeletal Muscle; Stimulus; Synaptic plasticity; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transducers; Transgenic Mice; Transgenic Organisms; Translations; aged; base; cell type; clinical investigation; cognitive benefits; cognitive function; differential expression; disease prognosis; drug repurposing; gene therapy; healthy aging; improved; innovation; mimetics; mouse model; neurogenesis; neuroinflammation; neuroprotection; neurotrophic factor; novel; novel therapeutic intervention; overexpression; pre-clinical; preservation; programs; proteostasis; proteotoxicity; response; systemic inflammatory response; tau Proteins; therapeutic development; tool; transcription factor; transcriptome; transcriptome sequencing; transcriptomics; transfer learning

ABSTRACT Skeletal muscle has recently arisen as a novel regulators of Central Nervous System (CNS) function and aging, secreting bioactive molecules known as myokines with proteostasis and metabolism-modifying functions in targeted tissues, including the CNS. Myokine secretion is heavily modified by exercise, suggesting that myokine signaling in the periphery may underlie the well documented geroprotective benefits of exercise on the brain. The following studies address muscle proteostasis, a pathway highly activated during exercise, as a potential new regulator of the neurocognitive benefits of exercise. We have recently generated a novel transgenic mouse with enhanced muscle proteostasis via moderate overexpression of Transcription Factor E-B (TFEB), a powerful master regulator of cellular clearance and proteostasis. We have discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity in the aging CNS and also improve cognition and memory in aging mice. Enhancing muscle proteostasis also reduced neuroinflammation and accumulation of AD-associated pathological hallmarks in plaque based and a tau- based models of AD. We have also identified previously unreported alterations in the transcriptome of skeletal muscle from patients with AD, as well as potential unique populations of skeletal muscle factors that may be driving these CNS benefits. In this project, we will determine if enhanced skeletal muscle proteostasis promotes neuroprotection against AD-associated phenotypes, and using powerful transfer learning and computational modeling approaches, identify exercise-associated circulating factors as new therapeutic interventions for the preservation of CNS function during AD.

抽象的 骨骼肌最近作为中枢神经系统（CNS）功能的新型调节剂而出现 衰老，分泌称为肌因子的生物活性分子，具有蛋白质稳态和代谢调节功能 在目标组织中，包括中枢神经系统。运动会严重改变肌因子的分泌，这表明 外周肌因子信号传导可能是运动对老年痴呆症有充分记录的益处的基础 大脑。以下研究涉及肌肉蛋白质稳态，这是一种在运动过程中高度激活的途径，作为 运动的神经认知益处的潜在新调节剂。我们最近创作了一本小说 通过适度过度表达转录因子 E-B 增强肌肉蛋白质稳态的转基因小鼠 (TFEB)，细胞清除和蛋白质稳态的强大主调节剂。我们发现， 由此产生的增强的骨骼肌蛋白质稳态功能可以显着改善衰老过程中的蛋白质毒性 中枢神经系统，还可以改善衰老小鼠的认知和记忆。增强肌肉蛋白质稳态也减少 基于斑块和 tau 的神经炎症和 AD 相关病理标志的积累 基于 AD 的模型。我们还发现了以前未报告的骨骼转录组变化 AD 患者的肌肉，以及可能与骨骼肌因子相关的潜在独特群体 推动这些中枢神经系统的益处。在这个项目中，我们将确定是否增强骨骼肌蛋白质稳态 促进针对 AD 相关表型的神经保护，并使用强大的迁移学习和 计算建模方法，将运动相关的循环因素确定为新的治疗方法 AD 期间保护中枢神经系统功能的干预措施。