The Role of NOX2-Mediated Oxidative Stress in Initiation of Acute Amyloid Toxicity

Although the role of NADPH oxidase 2 (NOX2) in the development of Alzheimer’s disease (AD) is widely recognized, its contribution to the initial stages of amyloid-induced pathology remains unclear. Intraventricular administration of β-amyloid (Aβ) causes acute amyloid toxicity, leading to neurodegenerative changes similar to AD. The acute phase, lasting several days, is a critical time window for studying early pathological mechanisms. In this work, we assessed the level of oxidative stress in the brain of BALB/c mice at the early stages of amyloid toxicity and the role of NOX2 in these processes. Analysis of key markers of oxidative stress in various fractions of brain homogenate on day 4 after Aβ administration showed that individual parameters demonstrated only a tendency to change, without reaching statistical significance. However, the principal component analysis (PCA) revealed a clear separation between the Aβ-treated and control groups, indicating the need for a comprehensive rather than isolated analysis of biochemical changes at early stages of pathology. It is noteworthy that the centroids of the groups in PCA were located along the same straight line, and the group receiving Aβ together with the NOX2 inhibitor occupied an intermediate position between the control and Aβ groups. This indicates a partial suppression of oxidative stress through NOX2. At the same time, the NOX2 inhibitor completely prevented Aβ-induced microgliosis in the hippocampus, confirming that the concentration used was sufficient to suppress NOX2-dependent microglial activation. The in vivo data demonstrate that oxidative stress induced by Aβ administration may be not entirely mediated by NOX2, although this mechanism plays an important role in the initiation of the pathological process in AD.

Amyloid toxicity, beta amyloid, NADPH oxidase, ROS, GSK2795039, glutathione, peroxidized lipids, microglia