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

Neuroreport. 1996 Dec 20;8(1):379-83. doi: 10.1097/00001756-199612200-00074.


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 beta-peptide (A beta) and increased vulnerability to A beta 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 A beta-induced apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Calcium / metabolism*
  • Calcium Channel Blockers / pharmacology
  • Cell Death / drug effects
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Homeostasis / physiology*
  • Membrane Proteins / genetics*
  • Muscarinic Antagonists / pharmacology
  • Mutation / physiology*
  • Nerve Degeneration / drug effects
  • Neurons / drug effects
  • PC12 Cells
  • Polymerase Chain Reaction
  • Presenilin-1
  • Rats
  • Receptors, Muscarinic / metabolism


  • Amyloid beta-Peptides
  • Calcium Channel Blockers
  • Membrane Proteins
  • Muscarinic Antagonists
  • Presenilin-1
  • Receptors, Muscarinic
  • Calcium