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Acute Interleukin‐6 Injection Influences Key Enzymes Involved in Amyloid Precursor Protein Processing in C57BL/6J Mice
Author(s) -
Marko Daniel,
Finch Michael,
Castellani Laura,
Peppler Willem,
Wright David,
MacPherson Rebecca
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03304
Subject(s) - amyloid precursor protein , amyloid precursor protein secretase , adam10 , hippocampus , amyloid beta , chemistry , endocrinology , beta (programming language) , medicine , amyloid (mycology) , enzyme , pharmacology , alzheimer's disease , biochemistry , pathology , disease , metalloproteinase , disintegrin , computer science , programming language
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.