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The Journal of Neuroscience, June 15, 2001, 21(12):4125-4133
 -Amyloid Activates the Mitogen-Activated Protein Kinase
Cascade via Hippocampal  7 Nicotinic Acetylcholine Receptors:
In Vitro and In Vivo Mechanisms Related
to Alzheimer's Disease
Kelly T.
Dineley1,
Marcus
Westerman3,
Duy
Bui1,
Karen
Bell1,
Karen Hsiao
Ashe2, 3, and
J. David
Sweatt1
1 Division of Neuroscience, Baylor College of Medicine,
Houston, Texas 77030, and Departments of 2 Neurology and
3 Neuroscience, University of Minnesota,
Minneapolis, Minnesota 55455
Alzheimer's Disease (AD) is the most common of the senile
dementias, the prevalence of which is increasing rapidly, with a projected 14 million affected worldwide by 2025. The signal
transduction mechanisms that underlie the learning and memory
derangements in AD are poorly understood.  -Amyloid (A) peptides
are elevated in brain tissue of AD patients and are the principal
component of amyloid plaques, a major criterion for postmortem
diagnosis of the disease. Using acute and organotypic hippocampal slice preparations, we demonstrate that A peptide 1-42 (A42) couples to
the mitogen-activated protein kinase (MAPK) cascade via  7 nicotinic
acetylcholine receptors (nAChRs). In vivo elevation of
A, such as that exhibited in an animal model for AD, leads to the
upregulation of 7 nAChR protein. 7 nAChR upregulation occurs
concomitantly with the downregulation of the 42 kDa isoform of
extracellular signal-regulated kinase (ERK2) MAPK in hippocampi of aged
animals. The phosphorylation state of a transcriptional mediator of
long-term potentiation and a downstream target of the ERK MAPK cascade,
the cAMP-regulatory element binding (CREB) protein, were affected
also. These findings support the model that derangement of
hippocampus signal transduction cascades in AD arises as a consequence
of increased A burden and chronic activation of the ERK MAPK cascade
in an 7 nAChR-dependent manner that eventually leads to the
downregulation of ERK2 MAPK and decreased phosphorylation of CREB protein.
Key words:
Alzheimer's disease; MAPK; nicotinic receptor; amyloid; kinase; hippocampus; learning; memory
Copyright © 2001 Society for Neuroscience 0270-6474/01/21124125-09$05.00/0
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