Caffeine stimulates amyloid β-peptide release from β-amyloid precursor protein-transfected HEK293 cells

Henry W. Querfurth, Jinwei Jiang, Jonathan D. Geiger, Dennis J. Selkoe

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

Extracellular amyloid β-peptide (Aβ) deposition is a pathological feature of Alzheimer's disease and the aging brain. Intracellular Aβ accumulation is observed in the human muscle disease, inclusion body myositis. Aβ has been reported to be toxic to neurons through disruption of normal calcium homeostasis. The pathogenic role of Aβ in inclusion body myositis is not as clear. Elevation of intracellular calcium following application of calcium ionophore increases the generation of Aβ from its precursor protein (βAPP). A receptor-based mechanism for the increase in Aβ production has not been reported to our knowledge. Here, we use caffeine to stimulate ryanodine receptor (RYR)-regulated intracellular calcium release channels and show that internal calcium stores also participate in the genesis of Aβ. In cultured HEK293 cells transfected with βAPP cDNA, caffeine (510 mM) significantly increased the release of Aβ fourfold compared with control. These actions of caffeine were saturable, modulated by ryanodine, and inhibited by the RYR antagonists ruthenium red and procaine. The calcium reuptake inhibitors thapsigargin and cyclopiazonic acid potentiated caffeine-stimulated Aβ release. NH4CI and monensin, agents that alter acidic gradients in intracellular vesicles, abolished both the caffeine and ionophore effects. Immunocytochemical studies showed some correspondence between the distribution patterns of RYR and cellular βAPP immunoreactivities. The relevance of these findings to Alzheimer's disease and inclusion body myositis is discussed.

Original languageEnglish (US)
Pages (from-to)1580-1591
Number of pages12
JournalJournal of Neurochemistry
Volume69
Issue number4
Publication statusPublished - Oct 1 1997

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Keywords

  • Alzheimer's disease
  • Amyloid β-Peptide
  • Caffeine
  • HEK293 cells
  • Inclusion body myositis
  • β-Amyloid precursor protein

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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