Neurotoxic effect of oligomeric and fibrillar species of amyloid β peptide 1-42: Involvement of endoplasmic reticulum calcium release in oligomer-induced cell death
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  . Aβ is strongly implicated in AD pathogenesis and is also linked to ER stress . Cultured neurons exposed to Aβ present increased levels of GRP78 . "
ABSTRACT: Neurodegenerative disorders such as Huntington's disease, amyotrophic lateral sclerosis and Parkinson's disease have in common the presence of protein aggregates in specific brain areas where significant neuronal loss is detected. In these pathologies, several evidences support a close correlation between neurodegeneration and endoplasmic reticulum (ER) stress, a condition that arises from ER lumen overload with misfolded proteins. Under these conditions, ER stress sensors initiate the unfolded protein response to restore normal ER function. If stress is too prolonged, or adaptive responses fail, apoptotic cell death ensues. Therefore, it was recently suggested that the manipulation of the ER unfolded protein response could be an effective strategy to avoid neuronal loss in neurodegenerative disorders. We will review the mechanisms underlying ER stress-associated neurodegeneration and discuss the possibility of ER as a therapeutic target.CNS & neurological disorders drug targets 04/2015; 14(4). DOI:10.2174/1871527314666150429112353 · 2.63 Impact Factor
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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. "
ABSTRACT: Early cognitive deficits in Alzheimer's disease (AD) seem to be correlated to dysregulation of glutamate receptors evoked by amyloid-beta (Aβ) peptide. Aβ interference with the activity of N-methyl-d-aspartate receptors (NMDARs) may be a relevant factor for Aβ-induced mitochondrial toxicity and neuronal dysfunction. To evaluate the role of mitochondria in NMDARs activation mediated by Aβ, we followed in situ single-cell simultaneous measurement of cytosolic free Ca(2+)(Cai(2+)) and mitochondrial membrane potential in primary cortical neurons. Our results show that direct exposure to Aβ + NMDA largely increased Cai(2+) and induced immediate mitochondrial depolarization, compared with Aβ or NMDA alone. Mitochondrial depolarization induced by rotenone strongly inhibited the rise in Cai(2+) evoked by Aβ or NMDA, suggesting that mitochondria control Ca(2+) entry through NMDARs. However, incubation with rotenone did not preclude mitochondrial Ca(2+) (mitCa(2+)) retention in cells treated with Aβ. Aβ-induced Cai(2+) and mitCa(2+) rise were inhibited by ifenprodil, an antagonist of GluN2B-containing NMDARs. Exposure to Aβ + NMDA further evoked a higher mitCa(2+) retention, which was ameliorated in GluN2B(-/-) cortical neurons, largely implicating the involvement of this NMDAR subunit. Moreover, pharmacologic inhibition of endoplasmic reticulum (ER) inositol-1,4,5-triphosphate receptor (IP3R) and mitCa(2+) uniporter (MCU) evidenced that Aβ + NMDA-induced mitCa(2+) rise involves ER Ca(2+) release through IP3R and mitochondrial entry by the MCU. Altogether, data highlight mitCa(2+) dyshomeostasis and subsequent dysfunction as mechanisms relevant for early neuronal dysfunction in AD linked to Aβ-mediated GluN2B-composed NMDARs activation. Copyright © 2014 Elsevier Inc. All rights reserved.Neurobiology of Aging 09/2014; 36(2). DOI:10.1016/j.neurobiolaging.2014.09.006 · 5.01 Impact Factor
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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. "
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.Frontiers in Molecular Neuroscience 11/2013; 6:36. DOI:10.3389/fnmol.2013.00036 · 4.08 Impact Factor