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

摘要 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，分泌生物活性分子，称为肌因子，具有蛋白质稳定和代谢调节功能 包括中枢神经系统。肌因子的分泌受到运动的严重影响，这表明， 外周肌细胞因子信号可能是运动对老年人的保护作用的基础。 大脑以下研究将肌肉蛋白质稳态（运动期间高度激活的途径）作为 运动对神经认知益处的潜在新调节剂。我们最近创作了一部小说 通过适度过表达转录因子E-B增强肌肉蛋白质稳态的转基因小鼠 （TFEB），一种强大的细胞清除和蛋白质稳定的主调节剂。我们发现， 由此产生的骨骼肌蛋白质稳态功能的增强可以显著改善衰老中的蛋白质毒性 中枢神经系统，并改善认知和记忆在老龄小鼠。增强肌肉蛋白质稳态也减少了 神经炎症和AD相关病理标志在斑块和tau蛋白中的积累， 基于AD的模型。我们还发现了以前未报道的骨骼肌转录组的改变， AD患者的肌肉，以及可能与AD相关的骨骼肌因子的潜在独特群体。 推动这些CNS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，确定运动相关的循环因子作为新的治疗方法， 在AD期间保护CNS功能的干预措施。

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.