Alzheimer's disease-associated peptide Aβ42 mobilizes ER Ca2+ via InsP3R-dependent and -independent mechanisms

被引:35
作者
Jensen, Laura E. [1 ]
Bultynck, Geert [2 ]
Luyten, Tomas [2 ]
Amijee, Hozeefa [3 ]
Bootman, Martin D. [1 ]
Roderick, H. Llewelyn [1 ]
机构
[1] Babraham Inst, Cambridge CB22 3AT, England
[2] Katholieke Univ Leuven, Dept Mol Cell Biol, Lab Mol & Cellular Signaling, Leuven, Belgium
[3] Senexis, Cambridge, England
来源
FRONTIERS IN MOLECULAR NEUROSCIENCE | 2013年 / 6卷
基金
英国生物技术与生命科学研究理事会;
关键词
Alzheimer's disease; A beta oligomers; calcium/Ca2+; InsP(3)/IP3; InsP(3) receptors/InsP(3)Rs; endoplasmic reticulum/ER; ENDOPLASMIC-RETICULUM STRESS; SOLUBLE AMYLOID OLIGOMERS; LONG-TERM POTENTIATION; A-BETA OLIGOMERS; MITOCHONDRIAL DYSFUNCTION; INTRACELLULAR CALCIUM; OXIDATIVE STRESS; COMMON MECHANISM; LIPID-BILAYERS; CELL-DEATH;
D O I
10.3389/fnmol.2013.00036
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Dysregulation of Ca2+ homeostasis is considered to contribute to the toxic action of the Alzheimer's disease (AD)-associated amyloid-beta-peptide (4). Ca2+ fluxes across the plasma membrane and release from intracellular stores have both been reported to underlie the Ca2+ fluxes induced by A beta(42). Here, we investigated the contribution of Ca2+ release from the endoplasmic reticulum (ER) to the effects of A beta(42) upon Ca2+ homeostasis and the mechanism by which A beta(42) elicited these effects. Consistent with previous reports, application of soluble oligomeric forms of A beta(42) induced an elevation in intracellular Ca2+. The A beta(42)-stimulated Ca2+ signals persisted in the absence of extracellular Ca2+ indicating a significant contribution of Ca2+ release from the ER Ca2+ store to the generation of these signals. Moreover, inositol 1,4,5-trisphosphate (InsP(3)) signaling contributed to A beta(42)-stimulated Ca2+ release. The Ca2+ mobilizing effect of A beta(42) was also observed when applied to permeabilized cells deficient in InsP(3) receptors, revealing an additional direct effect of A beta(42) upon the ER, and a mechanism for induction of toxicity by intracellular A beta(42).
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页数:12
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