Microglia, the resident macrophages in the brain, are strongly implicated in the progressive nature of Alzheimer’s disease (AD). In response to amyloid-â (Aâ) and neuronal damage, microglia produce toxic factors, such as cytokines and reactive oxygen species (ROS), which are then toxic to neighboring neurons. NADPH oxidase is an enzyme complex in microglia that generates neurotoxic ROS, amplifies the pro-inflammatory cytokine response, and contributes to progressive neurotoxicity. Recently, we have identified several inhibitors of NADPH oxidase that are neuroprotective in other disease models through attenuation of microglial activation. Here, using mutant human amyloid precursor protein (hAPP) transgenic mice as an in vivo model of AD, we will test whether our lead NADPH oxidase inhibitors are anti-inflammatory and neuroprotective. The results from this in vivo approach will establish the pre-clinical proof of concept that targeting microglial NADPH oxidase suppresses Aâ-induced neuroinflammation and ROS in vivo, with a consequent reduction of neuronal damage and dysfunction.