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The Journal of Neuroscience, June 15, 1998, 18(12):4451-4460
 -Amyloid Fibrils Activate Parallel Mitogen-Activated Protein
Kinase Pathways in Microglia and THP1 Monocytes
Douglas R.
McDonald,
Maria E.
Bamberger,
Colin K.
Combs, and
Gary E.
Landreth
Alzheimer Research Laboratory, Department of Neurology and
Neurosciences, Case Western Reserve University School of Medicine,
Cleveland, Ohio 44106
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  -amyloid (A),
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 A-induced inflammatory events are not well characterized.
We report that exposure of primary rat microglia and human THP1
monocytes to fibrillar A results in the tyrosine kinase-dependent activation of two parallel signal transduction cascades involving members of the mitogen-activated protein kinase (MAPK) superfamily. A 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 A.
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 A resulted in
the activation of RSK1 and RSK2 and phosphorylation of cAMP response
element-binding protein at Ser133, providing a
mechanism for A-induced changes in gene expression.
Key words:
Alzheimer's disease; -amyloid; microglia; THP1
monocytes; signal transduction; tyrosine kinase; MAPK superfamily; piceatannol; inflammatory; RAGE; scavenger receptor
Copyright © 1998 Society for Neuroscience 0270-6474/98/18124451-10$05.00/0
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