Abstract
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 Aβ1-42-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 Aβ1-42 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.
Highlights
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
We show that NADPH oxidase (NOX) activation by oligomeric Aβ1-42 results in pathological changes in brain glucose consumption, hippocampal network hyperactivity, and neuropsychiatric-like disturbances in mouse behavior
While NADPH oxidase 2 (NOX2) in microglia is activated in response to neurotoxic stimulation[25], NMDA receptor stimulation is required for NOX2 activation in neurons[46], and we found that NMDAR blockade recapitulated the effect of NOX2 inhibition (Supplementary Fig. 4)
Summary
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. We utilize a combination of electrophysiology with real-time recordings of metabolic transients both ex- and in-vivo to show that Aβ1-42 induces oxidative stress and acutely reduces cellular glucose consumption followed by longlasting network hyperactivity and abnormalities in the animal behavioral profile. All of these pathological changes were prevented by the novel bioavailable NOX2 antagonist GSK2795039. Glucose hypometabolism is implicated in the initiation of sporadic AD as it is associated with most major AD risk factors[10,11,12,13] It occurs in patients with amnestic mild cognitive impairment (aMCI), widely thought to be a prodromal stage of AD10,14,15, and has been detected in AD patients almost two decades prior to the onset of clinical symptoms. Our results point to early intervention in NOX-induced oxidative stress as a potential effective approach to AD prevention and treatment
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