β-Amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 monocytes

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Abstract

The senile plaques of Alzheimer's disease are foci of local inflammatory responses, as evidenced by the presence of acute phase proteins and oxidative damage. Fibrillar forms of β-amyloid (Aβ), which are the primary constituents of senile plaques, have been shown to activate tyrosine kinase- dependent signal transduction cascades, resulting in inflammatory responses in microglia. However, the downstream signaling pathways mediating Aβ- induced inflammatory events are not well characterized. We report that exposure of primary rat microglia and human THP1 monocytes to fibrillar Aβ results in the tyrosine kinase-dependent activation of two parallel signal transduction cascades involving members of the mitogen-activated protein kinase (MAPK) superfamily. Aβ stimulated the rapid, transient activation of extracellular signal-regulated kinase 1 (ERK1) and ERK2 in microglia and ERK2 in THP1 monocytes. A second superfamily member, p38 MAPK, was also activated with similar kinetics. Scavenger receptor and receptor for advanced glycated end products (RAGE) ligands failed to activate ERK and p38 MAPK in the absence of significant increases in protein tyrosine phosphorylation, demonstrating that scavenger receptors and RAGE are not linked to these pathways. Importantly, the stress-activated protein kinases (SAPKs) were not significantly activated in response to Aβ. Downstream effectors of the MAPK signal transduction cascades include MAPKAP kinases, such as RSK1 and RSK2, as well as transcription factors. Exposure of microglia and THP1 monocytes to Aβ resulted in the activation of RSK1 and RSK2 and phosphorylation of cAMP response element-binding protein at Ser133, providing a mechanism for Aβ- induced changes in gene expression.

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CITATION STYLE

APA

McDonald, D. R., Bamberger, M. E., Combs, C. K., & Landreth, G. E. (1998). β-Amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 monocytes. Journal of Neuroscience, 18(12), 4451–4460. https://doi.org/10.1523/jneurosci.18-12-04451.1998

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