Muscle Cathepsin B benefits Alzheimer's Disease mice

Muscle secretes factors during exercise that enhance cognition. Myokine Cathepsin B (Ctsb) is linked to memory, but its role in neurodegeneration is unclear. Here we show that AAV-vector-mediated Ctsb overexpression in skeletal muscle, in an Alzheimer’s Disease (AD) mouse model (APP/PS1), improved motor coordination, memory and adult hippocampal neurogenesis, while plaque density was unchanged. Conversely, in wildtype (WT) mice Ctsb impaired memory. To understand underlying mechanisms, hippocampus, muscle and plasma proteomic analyses were performed. In AD mice, Ctsb treatment increased abundance of hippocampal proteins involved in mRNA metabolism and protein synthesis. In muscle, Ctsb treatment increased protein translation in AD mice, whereas in WT mitochondrial proteins decreased. Additionally, in AD mice Ctsb enhanced plasma metabolic and mitochondrial processes, and reduced inflammatory responses. The differing protein abundance profiles in the AD and WT treatment groups correspond to effects on memory function. Overall, skeletal muscle Ctsb expression is a potential AD therapeutic.

肌肉在运动过程中可分泌增强认知功能的因子。肌因子组织蛋白酶B（Cathepsin B, Ctsb）与记忆功能相关，但其在神经退行性病变中的作用尚未明确。本研究在阿尔茨海默病（Alzheimer’s Disease, AD）APP/PS1小鼠模型中，通过腺相关病毒（Adeno-associated virus, AAV）载体介导骨骼肌过表达Ctsb，结果显示小鼠的运动协调能力、记忆功能及成年海马神经发生均得到改善，而脑内淀粉样斑块密度无显著变化。与之相反，在野生型（Wildtype, WT）小鼠中，骨骼肌过表达Ctsb会损伤其记忆能力。为探究其潜在分子机制，本研究对海马组织、骨骼肌及血浆进行了蛋白质组学分析。在AD模型小鼠中，Ctsb处理上调了海马组织中参与mRNA代谢与蛋白质合成的蛋白丰度；在骨骼肌中，AD模型小鼠经Ctsb处理后蛋白质翻译过程增强，而野生型小鼠的线粒体相关蛋白丰度则有所下降。此外，AD模型小鼠经Ctsb处理后，血浆中的代谢与线粒体相关过程得到强化，同时炎症反应得以减轻。AD模型组与野生型组间的蛋白质丰度差异谱，与两组小鼠的记忆功能变化相契合。综上，骨骼肌Ctsb的表达有望成为阿尔茨海默病的潜在治疗手段。