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

Post-exercise serum contained significantly elevated levels of multiple circulating factors compared to pre-exercise serum.

• Post-exercise serum showed increased amounts of Lactate, BDNF, IL-6, sAβPPα, and Aβ1-42 (p < 0.05)
• Post-exercise serum also showed reduced neprilysin activity (p < 0.05)
• Serum was collected before and immediately after high-intensity exercise
• These circulating factors were measured in serum used to treat iPSC-derived neural cells

Treatment with post-exercise serum acutely elevated ADAM10 activity in neurons.

• Both healthy control and familial AD (PSEN1 A246E) neurons were exposed to 10% pre- or post-exercise serum for 30 minutes
• ADAM10 is a key enzyme in the non-amyloidogenic processing pathway of AβPP
• The elevation of ADAM10 activity following post-exercise serum treatment was a statistically significant finding
• This effect was replicated by spiking lactate into pre-exercise serum, suggesting lactate as a potential mediating factor

Lactate spiked into pre-exercise serum replicated the ADAM10 activity increase seen with post-exercise serum in neurons.

• Pre-exercise serum was artificially supplemented with lactate to mimic post-exercise lactate levels
• This lactate-spiked pre-exercise serum reproduced the elevation of ADAM10 activity observed with post-exercise serum
• This finding implicates lactate as one of the circulating exercise-induced factors responsible for modulating AβPP processing
• Lactate was among the factors found to be elevated in post-exercise serum (p < 0.05)

sAβPPα was increased in PSEN1 familial AD neurons following post-exercise serum treatment.

• PSEN1 A246E neurons were exposed to 10% post-exercise serum for 30 minutes
• Increased sAβPPα in PSEN1 neurons indicates a shift toward non-amyloidogenic AβPP processing following post-exercise serum treatment
• The increase was statistically significant (p < 0.05)
• sAβPPα is a product of α-secretase (ADAM10) cleavage and is considered neuroprotective

Post-exercise serum treatment increased Aβ1-42 secretion in both PSEN1 neurons and astrocytes.

• Increased Aβ1-42 secretion was observed in both PSEN1 familial AD neurons and astrocytes following post-exercise serum treatment (p < 0.05)
• Cells were treated with 10% pre- or post-exercise serum for 30 minutes
• Aβ1-42 was also found to be elevated in post-exercise serum itself prior to cell treatment
• This finding represents a potentially adverse effect of post-exercise serum on amyloidogenic processing, particularly relevant to familial AD models

Human iPSC-derived neurons and astrocytes from both healthy controls and familial AD (PSEN1 A246E) mutation carriers were used as the cellular model.

• Both healthy control and familial AD (PSEN1 A246E) neurons and astrocytes were independently exposed to serum treatments
• Cells were treated with 10% pre- or post-exercise serum for 30 minutes
• Markers of AβPP processing were quantified following serum treatment
• Use of iPSC-derived human neural cells allows investigation of exercise effects in a human-relevant cellular context

Regular exercise is associated with reduced risk of Alzheimer's disease, potentially through limiting Aβ accumulation, but the underlying cellular mechanisms remain unclear.

• The number of people living with AD is increasing worldwide as populations age
• A hallmark of AD is the accumulation of amyloid-β (Aβ) in the brain
• Pathways regulating AβPP processing are of major interest for disease-modifying and preventive strategies such as exercise
• Acute bouts of exercise induce the release of circulating signalling molecules that may influence AβPP metabolism