Lactate increases ADAM10 activity and reduces BACE1 activity in mouse brain

Area of Science:

• Neuroscience
• Biochemistry
• Exercise Physiology

Background:

• Accumulation of beta-amyloid (Aβ) peptides contributes to neuronal dysfunction and death.
• Amyloid precursor protein (APP) processing occurs via two pathways: neuroprotective (ADAM10) and Aβ-producing (BACE1).
• Aerobic exercise is known to reduce BACE1 activity, but the underlying mechanisms, potentially involving lactate, are unclear.

Purpose of the Study:

• To investigate whether systemic lactate influences amyloid precursor protein (APP) processing.
• To determine if lactate affects the activity of beta-secretase 1 (BACE1) and alpha-secretase 10 (ADAM10).
• To explore the role of lactate as a mediator of exercise-induced changes in APP processing enzymes.

Main Methods:

• Mice were divided into four groups: sedentary, lactate-injected, exercise, and exercise with oxamate (a lactate dehydrogenase inhibitor).
• APP processing enzymes (BACE1 and ADAM10) activity and BACE1 protein content were measured in the hippocampus and prefrontal cortex (PFC).
• Interventions included a single lactate injection or an exercise bout, with measurements taken two hours post-intervention.

Main Results:

• In the PFC, both lactate injection and exercise increased ADAM10 activity compared to sedentary controls.
• In the hippocampus, lactate injection significantly increased ADAM10 activity, an effect abolished by oxamate.
• Hippocampal BACE1 activity was lower in the lactate group than in the exercise group, and oxamate increased BACE1 protein content in the PFC.

Conclusions:

• Systemic lactate accumulation appears to regulate ADAM10 activity, promoting a shift in APP processing away from Aβ production.
• Lactate may serve as a key mediator for exercise-induced alterations in APP processing enzymes.
• These findings highlight lactate's potential role in modulating neurodegenerative pathways associated with Aβ.