AMYLOID FIBRILS ACTIVATE TYROSINE KINASE-DEPENDENT SIGNALING AND SUPEROXIDE PRODUCTION IN MICROGLIA

Alzheimer's disease (AD) is a devastating neurological disorder charac terized by loss of cognitive skills and progressive dementia. The path ological hallmark of AD is the presence of numerous senile plaques thr oughout the hippocampus and cerebral cortex associated with degenerati ng axons, neurofibrillary tangles, and gliosis. The core of the senile plaque primarily is composed of the 39-43 amino acid beta-amyloid pep tide (A beta), which forms fibrils of beta-pleated sheets. Although co nsiderable genetic evidence implicates A beta in the pathogenesis of A D a direct causal link remains to be established. Senile plaques are f ool of local inflammatory processes, as evidenced by the presence of n umerous activated microglia and acute phase proteins. A beta has been shown to elicit inflammatory responses in microglia; however, the intr acellular events mediating these effects are largely unknown. We repor t that exposure of microglia and THP1 monocytes to fibrillar A beta le d to time- and dose-dependent increases in protein tyrosine phosphoryl ation of a population of proteins similar to that elicited by classica l immune stimuli such as immune complexes. The tyrosine kinases Lyn, S yk, and FAK were activated on exposure of microglia and THP1 monocytes to A beta resulting in the tyrosine kinase-dependent generation of su peroxide radicals. The present data support a role for oxidative damag e in the pathogenesis of AD, provide an important mechanistic link bet ween A beta and the generation of reactive oxygen intermediates, and i dentify molecular targets for therapeutic intervention in AD.