Lactate increases ADAM10 activity and reduces BACE1 activity in mouse brain

The accumulation and aggregation of beta-amyloid (Aβ) peptides contributes to neuronal dysfunction and death. These Aβ peptides originate from a transmembrane protein known as amyloid precursor protein (APP), which can be processed via two competing pathways. Alpha-secretase (ADAM10) cleavage is thought to be neuroprotective while beta-secretase (BACE1) cleavage results in the production of Aβ. Aerobic exercise reduces BACE1 activity, but the mechanisms involved are unknown though several exercise-induced mediators such as lactate may be involved. The current study examined whether systemic lactate can alter APP processing and BACE1 and ADAM10 activity. Mice were randomly assigned to one of four groups (n = 10 per group): (1) sedentary; (2) lactate-injection (1.0 g kg^-1 body mass); (3) exercise; and (4) exercise and oxamate (lactate dehydrogenase inhibitor; 750 mg kg^-1 body mass). Two hours following intervention, the hippocampus and prefrontal cortex (PFC) were collected. In the PFC lactate-injection and exercise resulted in higher ADAM10 activity compared to sedentary (exercise P = 0.0215, lactate P = 0.0038), in the hippocampus lactate-injection was higher compared to sedentary (lactate P = 0.011), and this was absent in the presence of oxamate. Hippocampal BACE1 activity was lower in the lactate group compared to the exercise group (P = 0.01). Oxamate resulted in higher BACE1 protein content compared to sedentary in the PFC (vs. sedentary P = 0.048). These findings suggest that lactate is important for regulating ADAM10 activity and thereby shifts APP processing away from Aβ production. KEY POINTS: Exercise is known to alter the processing of amyloid precursor protein by reducing the activity of the rate-limiting enzyme BACE1 and increasing the activity of ADAM10. It is thought that exercise-induced factors are responsible for these enzymatic changes. This study examined if lactate accumulation plays a role in this process. Mice were assigned to one of four groups: sedentary, lactate, exercise and exercise + lactate. The findings demonstrate that lactate accumulation alters brain BACE1 and ADAM10 and shifts amyloid precursor protein processing away from beta-amyloid production.