The p38 MAPK pathway is activated in a model of neurodegeneration in the rat in vivo

We investigated the role of inflammation in AD in an in vivo model of neuronal degeneration by injecting β-amyloid peptide (Aβ1-42, 5 μg/μl H2O) into the nucleus basalis of rats. This treatment results in cholinergic hypofunction that mimicks the cholinergic deficits of AD. Our interest was focussed in the understanding of the signal transduction pathways involved in this model of neurodegeneration. Three major MAP kinases (p42/p44, p38, and SAP/JUNK) have been shown to participate in inflammatory mechanisms. To investigate which of these pathways are involved, immunohistochemistry with antibodies for the phosphorylated form of the above kinases was performed on brain slices of rats injected with Aβ1-42. An inflammatory reaction was observed around the injected area, with activated microglia and production of inflammatory mediators. Numerous cells positive to the phospho-p38 MAPK were observed 7 and 30 days after injection and the selective COX-2 inhibitor rofecoxib (3 mg/kg/day) reduced p38 MAPK activation to control levels at either time. Confocal laser microscopy imaging of slices double labeled with anti-phospho p38 MAPK and anti-GFAP or -OX-6 showed colocalization, although partial, of phospho-p38 MAPK with OX-6, but not with GFAP, indicating that the p38 MAPK cascade is activated in microglia, but not astrocytes. The activation of p38 MAPK is one of the signal transduction pathways leading to increased production of COX-2, IL-1β, and other inflammatory mediators, possibly activating a vicious circle that amplifies the inflammatory reaction and leading to neurodegeneration.