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Exercise reduces cognitive aging, neurodegeneration, and Alzheimer's disease (AD) risk. Acute exercise reduces the activity of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), the rate-limiting enzyme in the production of Aβ. However, mechanisms mediating these effects remain largely unknown. Work has implicated brain-derived neurotrophic factor (BDNF) in the processing of amyloid precursor protein (APP). BDNF is an exercise-induced neurotrophin known for its role in synaptic plasticity, neurite growth, and neuronal survival. Previously, our lab has shown using an ex vivo model that treatment of the prefrontal cortex with BDNF reduced BACE1 activity, highlighting a BDNF to BACE1 link. The purpose of this research was to examine whether BDNF treatments resulted in similar biochemical adaptations to APP processing as exercise training. Male C57BL6/J mice were assigned into one of four groups ( n = 12/group): 1 ) control; 2 ) exercise training (progressive treadmill training 5 days/wk); 3 ) BDNF (0.5 mg/kg body mass subcutaneous injection 5 days/wk); or 4 ) endurance training and BDNF, for an 8-wk intervention. Recognition memory was measured with a novel object recognition test. Serum, the prefrontal cortex, and hippocampus were collected. BDNF improved recognition memory to a similar extent as endurance training. BDNF and exercise decreased BACE1 activity and increased ADAM10 activity in the prefrontal cortex, indicating a shift in APP processing. Our novel results indicate that BDNF exerts similar beneficial effects on cognition and APP processing as exercise training. Future evidence-based preventative or therapeutic interventions that increase BDNF and reduce BACE1 will be of value for populations that are at risk of AD. NEW & NOTEWORTHY Our study presents the novel findings that chronic peripheral BDNF injections result in regulation of APP processing enzymes and improved cognition to a similar extent as exercise training. These findings highlight the potential efficacy of using BDNF as a therapeutic intervention in the prevention of neurodegenerative diseases (i.e., Alzheimer's disease). Furthermore, future evidence-based preventative or therapeutic interventions that increase BDNF and reduce BACE1 will be of value for populations that are at risk of AD.

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 Socs3 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. NEW & NOTEWORTHY 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.