Investigating the effects of post-exercise serum treatments on APP processing in iPSC-derived neurons and astrocytes

The number of people living with Alzheimer's disease (AD) is increasing worldwide as populations age. A hallmark of AD is the accumulation of amyloid-β (Aβ) in the brain, and pathways regulating amyloid-β precursor protein (AβPP) processing are of major interest for disease-modifying and preventive strategies such as exercise. Regular exercise is associated with a reduced risk of AD, potentially through limiting Aβ accumulation, yet the underlying cellular mechanisms remain unclear. Acute bouts of exercise induce the release of circulating signalling molecules that may influence AβPP metabolism. To investigate the effects of exercise on AβPP processing, human induced pluripotent stem cell (iPSC)-derived neurons and astrocytes were treated with serum collected before and immediately after high-intensity exercise. Both healthy control and familial AD (PSEN1 A246E) neurons and astrocytes were independently exposed to 10 % pre- or post-exercise serum for 30 min, after which markers of AβPP processing were quantified. Post-exercise serum contained increased amounts of Lacate, BDNF, IL-6, sAβPPα, and Aβ₁-₄₂, and reduced neprilysin activity (p < 0.05). Treatment with post-exercise serum acutely elevated ADAM10 activity in neurons, which was replicated by spiking lactate in pre-exercise serum. sAβPPα was also increased in PSEN1 neurons following post exercise serum treatment with increased Aβ₁-₄₂ secretion in both PSEN1 neurons and astrocytes (p < 0.05). These findings demonstrate that human post-exercise serum can modulate AβPP processing in iPSC-derived neural cells. This supports the concept that circulating exercise-induced factors can influence neuronal pathways relevant to AD pathology.