A Beta Initiates Brain Hypometabolism, Network Dysfunction And Behavioral Abnormalities Via Nox2-Induced Oxidative Stress In Mice

A predominant trigger and driver of sporadic Alzheimer's disease (AD) is the synergy of brain oxidative stress and glucose hypometabolism starting at early preclinical stages. Oxidative stress damages macromolecules, while glucose hypometabolism impairs cellular energy supply and antioxidant defense. However, the exact cause of AD-associated glucose hypometabolism and its network consequences have remained unknown. Here we report NADPH oxidase 2 (NOX2) activation as the main initiating mechanism behind A beta(1-42)-related glucose hypometabolism and network dysfunction. We utilize a combination of electrophysiology with real-time recordings of metabolic transients both ex- and in-vivo to show that A beta(1-42) induces oxidative stress and acutely reduces cellular glucose consumption followed by long-lasting network hyperactivity and abnormalities in the animal behavioral profile. Critically, all of these pathological changes were prevented by the novel bioavailable NOX2 antagonist GSK2795039. Our data provide direct experimental evidence for causes and consequences of AD-related brain glucose hypometabolism, and suggest that targeting NOX2-mediated oxidative stress is a promising approach to both the prevention and treatment of AD.Anton Malkov, Irina Popova et al. demonstrate that beta-amyloid application induces oxidative stress and reduces glucose consumption in the mouse brain, leading to network hyperactivity and behavioral changes-pathologies similar to those observed early on in Alzheimer's disease patients. Inhibition of NADPH oxidase 2 (NOX2) rescued these phenotypes, suggesting that NOX2 may represent an important therapeutic target for Alzheimer's disease.