Neurotoxic effect of oligomeric and fibrillar species of amyloid β peptide 1-42: Involvement of endoplasmic reticulum calcium release in oligomer-induced cell death

Institute of Biochemistry, Faculty of Medicine and Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
Neuroscience (Impact Factor: 3.36). 07/2008; 155(3):725-37. DOI: 10.1016/j.neuroscience.2008.06.036
Source: PubMed

ABSTRACT The nature of the toxic form of amyloid-beta peptide (Abeta) involved in early Alzheimer's disease (AD) pathology and whether it is the fibrillar or the oligomeric peptide that is the most deleterious to neurons remain controversial. This work aimed to compare the neurotoxicity of different amyloid-beta peptide 1-42 (Abeta1-42) assemblies, using fresh and aged samples enriched in oligomeric and fibrillar species, respectively, and also isolated oligomers and fibrils. The results obtained with fresh and aged Abeta1-42 preparations suggested that oligomeric species are more toxic to cortical neurons in culture than fibrillar forms, which was confirmed by using isolated oligomers and fibrils. In order to further elucidate the mechanisms involved in soluble Abeta toxicity, the involvement of endoplasmic reticulum (ER) calcium (Ca(2+)) release in oligomer-induced apoptosis was evaluated. We observed that oligomeric Abeta1-42 depletes ER Ca(2+) levels leading to intracellular Ca(2+) dyshomeostasis involving phospholipase C activation. Moreover, in the presence of dantrolene, an inhibitor of ER Ca(2+) release through ryanodine receptors, the oligomer-induced apoptosis was prevented demonstrating the involvement of ER Ca(2+) release.

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    • "Moreover, a positive correlation between brain levels of the ER chaperone GRP78 and Braak staging was shown in AD patients [5] [116]. Aβ is strongly implicated in AD pathogenesis and is also linked to ER stress [118]. Cultured neurons exposed to Aβ present increased levels of GRP78 [119]. "
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    • "Ab induces an increase in Ca 2þ i and an immediate mitochondrial depolarization in cortical neurons, mediated by GluN2B-containing NMDA receptor (NMDAR) activation. Ca 2þ entry through NMDAR is taken up by the endoplasmic reticulum (Costa et al., 2012), which may be released by the inositol-1,4,5-triphosphate receptor (IP 3 R) (Resende et al., 2008). After exposure to Ab þ NMDA, Ca 2þ i increase is potentiated, inducing mitochondrial depolarization and enhanced mitochondrial Ca 2þ retention through a pathway that involves the release of Ca 2þ through IP 3 R and the entry to the mitochondria by the mitCa 2þ uniporter. "
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    • "Not only does caffeine inhibit InsP3Rs directly (Bezprozvanny et al., 1994), by also inhibiting PLC, caffeine is a potent inhibitor of InsP3 generation (Taylor and Broad, 1998). These findings are consistent with the reduction in the Aβ42-induced Ca2+ transient observed following application of the PLC inhibitor U73122 (Resende et al., 2008) although U73122 has numerous non-specific effects. The mechanism by which InsP3 signaling is engaged by Aβ42 in this study remains to be established. "
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    ABSTRACT: Dysregulation of Ca(2+) homeostasis is considered to contribute to the toxic action of the Alzheimer's disease (AD)-associated amyloid-β-peptide (Aβ). Ca(2+) fluxes across the plasma membrane and release from intracellular stores have both been reported to underlie the Ca(2+) fluxes induced by Aβ42. Here, we investigated the contribution of Ca(2+) release from the endoplasmic reticulum (ER) to the effects of Aβ42 upon Ca(2+) homeostasis and the mechanism by which Aβ42 elicited these effects. Consistent with previous reports, application of soluble oligomeric forms of Aβ42 induced an elevation in intracellular Ca(2+). The Aβ42-stimulated Ca(2+) signals persisted in the absence of extracellular Ca(2+) indicating a significant contribution of Ca(2+) release from the ER Ca(2+) store to the generation of these signals. Moreover, inositol 1,4,5-trisphosphate (InsP3) signaling contributed to Aβ42-stimulated Ca(2+) release. The Ca(2+) mobilizing effect of Aβ42 was also observed when applied to permeabilized cells deficient in InsP3 receptors, revealing an additional direct effect of Aβ42 upon the ER, and a mechanism for induction of toxicity by intracellular Aβ42.
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