BETA-AMYLOID FIBRILS ACTIVATE PARALLEL MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAYS IN MICROGLIA AND THP1 MONOCYTES

The senile plaques of Alzheimer's disease are foci of local inflammato ry responses, as evidenced by the presence of acute phase proteins and oxidative damage. Fibrillar forms of beta-amyloid (A beta), which are the primary constituents of senile plaques, have been shown to activa te tyrosine kinase-dependent signal transduction cascades, resulting i n inflammatory responses in microglia. However, the downstream signali ng pathways mediating A beta-induced inflammatory events are not well characterized. We report that exposure of primary rat microglia and hu man THP1 monocytes to fibrillar A beta results in the tyrosine kinase- dependent activation of two parallel signal transduction cascades invo lving members of the mitogen-activated protein kinase (MAPK) superfami ly. A beta stimulated the rapid, transient activation of extracellular signal-regulated kinase 1 (ERK1) and ERK2 in microglia and ERK2 in TH P1 monocytes. A second superfamily member, p38 MAPK, was also activate d with similar kinetics. Scavenger receptor and receptor for advanced glycated end products (RAGE) ligands failed to activate ERK and p38 MA RK in the absence of significant increases in protein tyrosine phospho rylation, demonstrating that scavenger receptors and RAGE are not link ed to these pathways. Importantly, the stress-activated protein kinase s (SAPKs) were not significantly activated in response to A beta. Down stream effecters of the MARK signal transduction cascades include MAPK AP kinases, such as RSK1 and RSK2, as well as transcription factors. E xposure of microglia and THP1 monocytes to A beta resulted in the acti vation of RSK1 and RSK2 and phosphorylation of cAMP response element-b inding protein at Ser(133), providing a mechanism for A beta-induced c hanges in gene expression.