Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms related to Alzheimer's disease.
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. beta-Amyloid (Abeta) 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 Abeta peptide 1-42 (Abeta42) couples to the mitogen-activated protein kinase (MAPK) cascade via alpha7 nicotinic acetylcholine receptors (nAChRs). In vivo elevation of Abeta, such as that exhibited in an animal model for AD, leads to the upregulation of alpha7 nAChR protein. alpha7 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 Abeta burden and chronic activation of the ERK MAPK cascade in an alpha7 nAChR-dependent manner that eventually leads to the downregulation of ERK2 MAPK and decreased phosphorylation of CREB protein.
Dineley
K T
KT
Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA. kdineley@cns.bcm.tmc.edu
Westerman
M
M
Bui
D
D
Bell
K
K
Ashe
K H
KH
Sweatt
J D
JD
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology; D006579:Heterozygote; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D020536:Enzyme Activators; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); D009538:Nicotine; D019950:Mitogen-Activated Protein Kinase 1