Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid beta-peptide.
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.
Guo
Q
Q
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230, USA.
Furukawa
K
K
Sopher
B L
BL
Pham
D G
DG
Xie
J
J
Robinson
N
N
Martin
G M
GM
Mattson
M P
MP
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009154:Mutation / Q000502:physiology*; D009410:Nerve Degeneration / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D016716:PC12 Cells; D016133:Polymerase Chain Reaction; D053764:Presenilin-1; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism
D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D008565:Membrane Proteins; D018727:Muscarinic Antagonists; D053764:Presenilin-1; D011976:Receptors, Muscarinic; D002118:Calcium