Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid β-peptide

Qing Guo, Katsutoshi Furukawa, Bryce L. Sopher, Dao G. Pham, Jun Xie, Nic Robinson, George M. Martin, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

Mutations in the presenilin-1 (PS-1) gene on chromosome 14 are linked to autosomal dominant early-onset Alzheimer's disease. The amino acid sequence of PS-1 predicts an integral membrane protein and immunocytochemical studies indicate that PS-1 is localized to endoplasmic reticulum (ER). We report that expression of PS-1 mutation L286V in cultured PC12 cells exaggerates Ca2+ responses to agonists (carbachol and bradykinin) that induce Ca2+ release from ER. Cells expressing L286V exhibit enhanced elevations of [Ca2+](i) following exposure to amyloid β-peptide (Aβ) and increased vulnerability to Aβ toxicity. An antagonist of voltage-dependent calcium channels (nifedipine), and a blocker of Ca2+ release from ER (dantrolene), counteract the adverse consequences of the PS-1 mutation. By perturbing Ca2+ homeostasis, PS-1 mutations may sensitize neurons to Aβ-induced apoptosis.

Original languageEnglish (US)
Pages (from-to)379-383
Number of pages5
JournalNeuroReport
Volume8
Issue number1
Publication statusPublished - 1997
Externally publishedYes

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Keywords

  • Apoptosis
  • Dantrolene
  • Endoplasmic reticulum
  • Fura-2
  • Muscarinic acetylcholine receptors
  • Nifedipine
  • Presenilin
  • Voltage-dependent calcium channels

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Guo, Q., Furukawa, K., Sopher, B. L., Pham, D. G., Xie, J., Robinson, N., ... Mattson, M. P. (1997). Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid β-peptide. NeuroReport, 8(1), 379-383.