Acute interleukin-6 modulates key enzymes involved in prefrontal cortex and hippocampal amyloid precursor protein processing.

Abstract

Exercise is 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 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 if acute IL-6 can modulate key enzymes responsible for APP processing, namely a disintegrin and metalloproteinase 10 (ADAM10) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), which initiate the non-amyloidogenic and amyloidogenic cascades respectively. Male 10-week-old C57BL/6J mice underwent and acute treadmill exercise bout or were either injected with 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 sAPPa and sAPPβ, were examined. Exercise increased circulating IL-6 and brain IL-6 signaling (pSTAT3 and Socs3 mRNA). This occurred alongside a reduction in BACE1 activity and an increase in ADAM10 activity. IL-6 injection reduced BACE1 activity and increased sAPPa 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 non-amyloidogenic cascade and decreases markers of the amyloidogenic cascade in the cortex and hippocampus of the brain.