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Volume 17, Number 7,
Issue of April 1, 1997
pp. 2284-2294
Copyright ©1997 Society for Neuroscience
Amyloid Fibrils Activate Tyrosine Kinase-Dependent Signaling and
Superoxide Production in Microglia
Received Sept. 24, 1996; revised Jan. 7, 1997; accepted Jan. 15, 1997.
Douglas R. McDonald1,
Kurt R. Brunden2, and
Gary
E. Landreth1
1 Alzheimer Research Laboratory, Department of
Neurology and Neurosciences, Case Western Reserve University School of
Medicine, Cleveland, Ohio 44106, and 2 Gliatech,
Incorporated, Cleveland, Ohio 44122
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
 -amyloid peptide (A), which forms fibrils of -pleated sheets.
Although considerable genetic evidence implicates A in the
pathogenesis of AD, a direct causal link remains to be established.
Senile plaques are foci of local inflammatory processes, as
evidenced by the presence of numerous activated microglia and acute
phase proteins. A 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 A 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 A, 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 A and the generation of
reactive oxygen intermediates, and identify molecular targets for
therapeutic intervention in AD.
Key words:
Alzheimer's disease;
-amyloid;
microglia;
THP1
monocytes;
signal transduction;
tyrosine kinase;
inflammatory;
superoxide;
piceatannol;
RAGE;
scavenger receptor
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