beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha 7 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 pr evalence of which is increasing rapidly, with a projected 14 million affect ed worldwide by 2025. The signal transduction mechanisms that underlie the learning and memory derangements in AD are poorly understood. beta -Amyloid (A beta) peptides are elevated in brain tissue of AD patients and are the principal component of amyloid plaques, a major criterion for postmortem di agnosis of the disease. Using acute and organotypic hippocampal slice prepa rations, we demonstrate that A beta peptide 1-42 (A beta 42) couples to the mitogen-activated protein kinase (MAPK) cascade via alpha7 nicotinic acety lcholine receptors (nAChRs). In vivo elevation of A beta, such as that exhi bited in an animal model for AD, leads to the upregulation of alpha7 nAChR protein. alpha7 nAChR upregulation occurs concomitantly with the downregula tion of the 42 kDa isoform of extracellular signal-regulated kinase (ERK2) MAPK in hippocampi of aged animals. The phosphorylation state of a transcri ptional mediator of long-term potentiation and a downstream target of the E RK MAPK cascade, the cAMP-regulatory element binding (CREB) protein, were a ffected also. These findings support the model that derangement of hippocam pus signal transduction cascades in AD arises as a consequence of increased A beta 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.