Acute Interleukin‐6 Injection Influences Key Enzymes Involved in Amyloid Precursor Protein Processing in C57BL/6J Mice

Abstract

Background Amyloid-beta plaques are a hallmark feature of Alzheimer's disease and are the product of aggregated amyloid-beta peptides. These peptides originate from amyloid precursor protein (APP) which is cleaved by beta secretase (BACE1), a key enzyme in the amyloidogenic cascade. Cleavage of APP by alpha secretase (ADAM10) however, does not result in amyloid-beta peptides and is a key enzyme in the non-amyloidogenic cascade. It is widely accepted that exercise reduces amyloid-beta production and plaque build-up in the brain, although it is unclear how exercise may be driving this observation. Interleukin-6 (IL-6) is an exercise induced cytokine and recent work in this area has demonstrated a role for acute exercise induced IL-6 in tissues such as muscle, adipose, and liver, however the role of acute IL-6 in the brain remains ill defined. The purpose of this study is to investigate if acute IL-6 injection will modulate key enzymes involved in APP processing, namely BACE1 and ADAM10. It is hypothesized that acute IL-6 injection will result in a shift towards the non-amyloidogenic processing of APP. Methods Male 10-week-old C57BL/6J mice were intraperitoneally injected with a weight-adjusted dose of recombinant murine IL-6 (3ng/g body mass) or an equivalent volume of saline. Brain tissue was acquired 15 minutes post-injection and the pre-frontal cortex and hippocampus regions were dissected. Results Acute IL-6 injection resulted in lower BACE1 activity in both the cortex (p=0.011) and the hippocampus (p=0.027) compared to the saline injected group. This was accompanied by lower BACE1 (p=0.007) and sAPPb(p=0.019) protein content in the hippocampus of mice injected with IL-6. No differences for BACE1 or sAPPb were observed in the cortex. ADAM10 activity was higher with IL-6 injection compared to saline in the hippocampus (p=0.018) and the cortex (p=0.055). A change in ADAM10 protein content was also observed with the ratio of pro to mature ADAM10 being higher in the cortex (p=0.033) of the IL-6 injected mice as compared to the saline injected control. Similarly, both pro (p=0.017) and mature (p=0.035) ADAM10 protein content were lower in the hippocampus of the IL-6 injected mice as compared to the saline injected control. Conclusions These results demonstrate that acute IL-6 modulates important enzymes involved in APP processing; pushing the cascade towards the non-amyloidogenic arm. This work further highlights regional brain differences in response to acute IL-6 and extends our knowledge of the function of acute IL-6 as a signalling molecule in the brain. Future work should determine if exercise induced IL-6 is in fact the main mediator of non-amyloidogenic APP processing.