Aβ-induced NOX2 activation underlies oxidative stress leading to brain hypometabolism and hyperactivity in Alzheimer’s disease

A paramount driver of sporadic Alzheimer’s disease (AD) is the synergy of oxidative stress and glucose hypometabolism in the brain. Oxidative stress damages cellular macromolecules such as DNA, lipids and proteins, whereas glucose hypometabolism impairs cellular energy supply and antioxidant defence; Together, these cellular and functional alterations may be primary triggers of AD. However, the exact molecular basis of AD-associated glucose hypometabolism has remained unknown, hampering the search for effective interventions. Here, we identify NADPH oxidase 2 (NOX2) activation by beta-amyloid peptide (Aβ) as the main molecular source of oxidative stress driving brain glucose hypometabolism and network hyperactivity. Using a combination of electrophysiology with dynamic recordings of autofluorescence and metabolic biosensors, we show that in hippocampal brain slices, Aβ application reduced network activity-driven glucose consumption and glycolysis by half, while NOX2 antagonism prevented this effect. , intracerebroventricular injection of Aβ exerted a profound inhibitory effect on brain glucose consumption, resulting in long-lasting network hyperactivity and changes in animal behavioral profile. Critically, the novel bioavailable NOX2 antagonist GSK2795039 prevented all of the observed Aβ-related detrimental effects. These data suggest that targeting NOX2-induced oxidative stress is a promising approach to both the prevention and treatment of AD.