Studies on the production of IL-1β, TNF-α, iNOS, IL-10, and ROS in the APP/PS1 mouse model of Alzheimer's disease

It is well known that excessive brain inflammation cause both acute and chronic neurodegeneration. Our previous study demonstrated the neuroprotective effects of IL-10 in LPS-injected rat cerebral cortex, which was mediated by inhibition of NADPH oxidase activation and pro-inflammatory mediators expression. Here, we observed the expression of pro-inflammatory mediators and IL-10 in the cerebral cortex of transgenic mouse model of AD (APP/PS1). In transgenic mice, microglia and astrocytes were activated synchronously with Aβ deposits and were abundant and closely associated with senile plaques. At 14-17 months, microglia and astrocytes were morphologically damaged and excessively activated. The mRNA and protein levels of IL-1β, TNF-α and iNOS were detected from 3 months, and they were increased with age. The mRNA and protein levels of IL-10 were detectable in 6 month-old transgenic mouse, which is 3 months later than the expression of pro-inflammatory mediators. Double immunoflorescence staining showed that IL-1β, TNF-α and IL-10 expression was localized mainly in Iba1-immunopositive microglia. Reactive oxygen species (ROS) production was detected from 6 months, and there most significantly increased between the ages of 14 months and 17 months. A major subunit of NADPH oxidase, gp91 phox protein was localized to Iba1-immunopositive microglia in the APP/PS1 transgenic mice. And also, cerebral cortex of ii 14, 17 months showed significant decrease in NeuN-positive neurons and MAP2-immunoreactice dendrites. These results suggest that activated microglia surrounding plaques induce excessive production of pro-inflammatory mediators and ROS, leading to neuronal damage.