MAPK recruitment by β-amyloid in organotypic hippocampal slice cultures depends on physical state and exposure time

Karen A. Bell, Kenneth J. O'Riordan, J. David Sweatt, Kelly T. Dineley

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

Elevated β-amyloid is thought to trigger the onset of Alzheimer's disease. Alzheimer's disease is marked by progressive loss of cognitive function, an early symptom of which is episodic memory deficits. Impairment of episodic memory is linked to hippocampal pathology. We investigated the signal transduction consequences of exposure to nanomolar to low micromolar concentrations of aggregate forms of β-amyloid in the hippocampus. We found that, in addition to activation of ERK MARK and its downstream target ribosomal S6 kinase in hippocampal slice cultures following acute exposure to oligomeric β-amyloid1-42, ERK activation also requires phosphoinositide-3 kinase activity. These effects were contingent on the α7 subtype of nicotinic acetylcholine receptor. Hippocampal slice cultures treated acutely with oligomeric β-amyloid1-42 did not exhibit JNK MARK activation; however, chronic exposure to oligomers or high molecular weight aggregates of β-amyloid1-42 led to JNK MARK activation coincident with ERK MARK down-regulation. In contrast to the effects of acute application of oligomeric β-amyloid1-42, nicotine activated ERK MARK via α7 nicotinic acetylcholine receptors utilizing protein kinase A as an intermediate. In conclusion, we found that both the physical state and duration of exposure to β-amyloid are determinants of MARK recruitment in hippocampus. We also found that nicotine and β-amyloid activate ERK MARK via α7 nicotinic acetylcholine receptors but use distinct intermediate kinases. These data indicate the existence of differential coupling of α7 to downstream targets depending on the type of ligand that leads to receptor activation.

Original languageEnglish (US)
Pages (from-to)349-361
Number of pages13
JournalJournal of neurochemistry
Volume91
Issue number2
DOIs
StatePublished - Oct 2004

Keywords

  • Alpha7
  • Alzheimer
  • Hippocampus
  • Nicotinic receptor
  • Oligomer

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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