Abstract:The p38 mitogen-activated protein kinase is a stress-activated enzyme responsible for transducing inflammatory signals and initiating apoptosis. In the Alzheimer's disease (AD) brain, increased levels of phosphorylated (active) p38 were detected relative to age-matched normal brain. Intense phospho-p38 immunoreactivity was associated with neuritic plaques, neuropil threads, and neurofibrillary tangle-bearing neurons. The antibody against phosphorylated p38 recognized many of the same structures as an antibody against aberrantly phosphorylated, paired helical filament (PHF) tau, although PHF-positive tau did not cross-react with the phosphop38 antibody. These findings suggest a neuroinflammatory mechanism in the AD brain, in which aberrant protein phosphorylation affects signal transduction elements, including the p38 kinase cascade, as well as cytoskeletal Alzheimer's disease (AD) is a progressive dementing disorder characterized by selective neuron loss in the limbic system and association regions of the neocortex. The characteristic histopathologic alterations in AD are neuritic or senile plaques (SPs) composed largely of amyloid P-peptides (AP) and neuronal aggregates of abnormally phosphorylated cytoskeletal proteins [neurofibrillary tangles (NFTs)] (GrundkeIqbal et al., 1986). Brain regions affected by AD also demonstrate hallmarks of inflammation, including elevated levels of proinflammatory cytokines (particularly interleukin-1 and -6), complement, and acutephase reactants (Rogers et a]., 1996); higher than normal levels of lipid, protein, and DNA oxidation (Smith et al., 1991;Mecocci et al., 1993;Smith et al., 1997;Hensley et al., 1998); and proliferation of microglial cells, which are functionally similar to monocytes (Itagaki et al., 1989). Epidemiological data indicate that long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) diminishes risk for AD (Carpenter et al., 1993), and clinical studies indicate that the antioxidant a-tocopherol as well as NSAIDs may slow the progression of the disease (Rich et al., 1995;Sano et al., 1997). Recent models for AD pathogenesis therefore propose that atypical forms of inflammation, perhaps initiated by an immune response to plaque deposition, engender oxidative stress and neuronal damage in sensitive brain regions. The principal weakness of the neuroinflammatory model is that specific biochemical mechanisms have not been discovered that might explain precisely how an inflammatory process can propagate chronically in the AD brain.Because inflammation is fundamentally an autocrine or paracrine process involving cytokine-mediated activation of gene expression in target cells, we reasoned that dysfunction of specific signal transduction pathways responsible for cytokine-, AP-, or oxidant-stimulated gene induction might engender chronic inflammatory and oxidative processes in AD. We now report evidence that the p38 mitogen-activated protein (MAP) kinase pathway, a major proinflammatory signal transduction pathway activated by oxidants, cytokines, and ...