Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia

Abstract

Alzheimer's disease (AD) is a devastating neurological disorder characterized by loss of cognitive skills and progressive dementia. The pathological hallmark of AD is the presence of numerous senile plaques throughout the hippocampus and cerebral cortex associated with degenerating axons, neurofibrillary tangles, and gliosis. The core of the senile plaque primarily is composed of the 39-43 amino acid β-amyloid peptide (Aβ), which forms fibrils of β-pleated sheets. Although considerable genetic evidence implicates Aβ in the pathogenesis of AD, a direct causal link remains to be established. Senile plaques are loci of local inflammatory processes, as evidenced by the presence of numerous activated microglia and acute phase proteins. Aβ has been shown to elicit inflammatory responses in microglia; however, the intracellular events mediating these effects are largely unknown. We report that exposure of microglia and THP1 monocytes to fibrillar Aβ led to time- and dose-dependent increases in protein tyrosine phosphorylation of a population of proteins similar to that elicited by classical immune stimuli such as immune complexes. The tyrosine kinases Lyn, Syk, and FAK were activated on exposure of microglia and THP1 monocytes to Aβ, resulting in the tyrosine kinase-dependent generation of superoxide radicals. The present data support a role for oxidative damage in the pathogenesis of AD, provide an important mechanistic link between Aβ and the generation of reactive oxygen intermediates, and identify molecular targets for therapeutic intervention in AD.