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J. Biol. Chem., Vol. 278, Issue 19, 17546-17556, May 9, 2003
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-Amyloid
Peptide-induced Signaling in Cortical Slices*
From the Department of Physiology and Biophysics, State University
of New York at Buffalo, School of Medicine and Biomedical Sciences,
Buffalo, New York 14214
Deposition of fibrillar aggregates of the
-amyloid peptide (A
) is a key pathologic feature during the early
stage of Alzheimer's disease. The initial neuronal responses to
A
in cortical circuits and the regulation of A
-induced signaling
remain unclear. In this study, we found that exposure of cortical
slices to A
1-42 or A
25-35 induced
a marked increase in the activation of protein kinase C (PKC) and
Ca2+/calmodulin-dependent kinase II (CaMKII),
two enzymes critically involved in a variety of cellular functions.
Activation of M1 muscarinic receptors, but not nicotinic receptors,
significantly inhibited the A
activation of PKC and CaMKII.
Increasing inhibitory transmission mimicked the M1 effect on A
,
whereas blocking GABAA receptors eliminated the M1 action.
Moreover, electrophysiological evidence shows that application of A
to cortical slices induced action potential firing and enhanced
excitatory postsynaptic currents, whereas muscarinic agonists potently
increased inhibitory postsynaptic currents. These results suggest that
A
activates PKC and CaMKII through enhancing excitatory activity in
glutamatergic synaptic networks. Activation of M1 receptors inhibits
A
signaling by enhancing the counteracting
GABAergic inhibitory transmission. Thus the
muscarinic reversal of the A
-induced biochemical and physiological
changes provides a potential mechanism for the treatment of
Alzheimer's disease with cholinergic enhancers.
To whom correspondence should be addressed: Dept. of Physiology
and Biophysics, State University of New York at Buffalo, 124 Sherman
Hall, Buffalo, NY 14214. E-mail: zhenyan@buffalo.edu.
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