β-Amyloid activates the mitogen-activated protein kinase cascade via hippocampal α7 nicotinic acetylcholine receptors: In Vitro and in Vivo mechanisms related to Alzheimer's disease

K. T. Dineley, M. Westerman, D. Bui, K. Bell, K. H. Ashe, J. D. Sweatt

Research output: Contribution to journalArticle

444 Scopus citations

Abstract

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. β-Amyloid (Aβ) 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 Aβ peptide 1-42 (Aβ42) couples to the mitogen-activated protein kinase (MAPK) cascade via α7 nicotinic acetylcholine receptors (nAChRs). In vivo elevation of Aβ, such as that exhibited in an animal model for AD, leads to the upregulation of α7 nAChR protein. α7 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 Aβ burden and chronic activation of the ERK MAPK cascade in an α7 nAChR-dependent manner that eventually leads to the downregulation of ERK2 MAPK and decreased phosphorylation of CREB protein.

Original languageEnglish (US)
Pages (from-to)4125-4133
Number of pages9
JournalJournal of Neuroscience
Volume21
Issue number12
StatePublished - Jun 15 2001
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Amyloid
  • Hippocampus
  • Kinase
  • Learning
  • MAPK
  • Memory
  • Nicotinic receptor

ASJC Scopus subject areas

  • Neuroscience(all)

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