Department of Health Sciences, Brock University, St. Catharines, Ontario, Canada.
Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
J Appl Physiol (1985). 2023 May 1;134(5):1115-1123. doi: 10.1152/japplphysiol.00520.2022. Epub 2023 Mar 9.
Exercise has been shown to be beneficial for individuals with Alzheimer's disease (AD). In rodent models of AD, exercise decreases the amyloidogenic processing of the amyloid precursor protein (APP). Although it remains unclear as to how exercise is promoting this shift away from pathological APP processing, there is emerging evidence that exercise-induced factors released from peripheral tissues may facilitate these alterations in brain APP processing. Interleukin-6 (IL-6) is released from multiple organs into peripheral circulation during exercise and is among the most characterized exerkines. The purpose of this study is to examine whether acute IL-6 can modulate key enzymes responsible for APP processing, namely, a disintegrin and metalloproteinase 10 (ADAM10) and β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), which initiate the nonamyloidogenic and amyloidogenic cascades, respectively. Male 10-wk-old C57BL/6J mice underwent acute treadmill exercise bout or were injected with either IL-6 or a PBS control 15 min prior to tissue collection. ADAM10 and BACE1 enzyme activity, mRNA, and protein expression, as well as downstream markers of both cascades, including soluble APPα (sAPPα) and soluble APPβ (sAPPβ), were examined. Exercise increased circulating IL-6 and brain IL-6 signaling (pSTAT3 and mRNA). This occurred alongside a reduction in BACE1 activity and an increase in ADAM10 activity. IL-6 injection reduced BACE1 activity and increased sAPPα protein content in the prefrontal cortex. In the hippocampus, IL-6 injection decreased BACE1 activity and sAPPβ protein content. Our results show that acute IL-6 injection increases markers of the nonamyloidogenic cascade and decreases markers of the amyloidogenic cascade in the cortex and hippocampus of the brain. It is becoming evident that exercise modulates APP processing and can reduce amyloid-beta (Aβ) peptide production. Our data help to explain this phenomenon by highlighting IL-6 as an exercise-induced factor that lowers pathological APP processing. These results also highlight brain regional differences in response to acute IL-6.
锻炼已被证明对阿尔茨海默病（AD）患者有益。在 AD 的啮齿动物模型中，锻炼可减少淀粉样前体蛋白（APP）的淀粉样生成处理。尽管尚不清楚锻炼如何促进这种病理性 APP 处理的转变，但有新的证据表明，来自外周组织的运动诱导因子可能促进大脑 APP 处理的这些改变。白细胞介素 6（IL-6）在运动期间从多个器官释放到外周循环中，是最具特征的细胞因子之一。本研究的目的是检查急性 IL-6 是否可以调节负责 APP 处理的关键酶，即解整合素金属蛋白酶 10（ADAM10）和β位淀粉样前体蛋白裂解酶 1（BACE1），它们分别启动非淀粉样生成和淀粉样生成级联。10 周龄雄性 C57BL/6J 小鼠进行急性跑步机运动或在组织采集前 15 分钟注射 IL-6 或 PBS 对照。检查 ADAM10 和 BACE1 酶活性、mRNA 和蛋白表达以及两个级联的下游标志物，包括可溶性 APPα（sAPPα）和可溶性 APPβ（sAPPβ）。运动增加了循环中的 IL-6 和大脑中的 IL-6 信号（pSTAT3 和 mRNA）。这伴随着 BACE1 活性的降低和 ADAM10 活性的增加。IL-6 注射降低了前额叶皮层中的 BACE1 活性和 sAPPα 蛋白含量。在海马体中，IL-6 注射降低了 BACE1 活性和 sAPPβ 蛋白含量。我们的结果表明，急性 IL-6 注射增加了大脑皮质和海马体中非淀粉样生成级联的标志物，并减少了淀粉样生成级联的标志物。运动调节 APP 处理并减少淀粉样β（Aβ）肽产生的现象越来越明显。我们的数据通过强调 IL-6 作为降低病理性 APP 处理的运动诱导因子，有助于解释这一现象。这些结果还突出了大脑对急性 IL-6 反应的区域差异。
