The release of calcium from the endoplasmic reticulum induced by amyloid-beta and prion peptides activates the mitochondrial apoptotic pathway

Center for Neuroscience and Cell Biology, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal.
Neurobiology of Disease (Impact Factor: 5.08). 07/2008; 30(3):331-42. DOI: 10.1016/j.nbd.2008.02.003
Source: PubMed


In this study, we analyzed whether ER Ca2+ release, induced by amyloid-beta (Abeta) and prion (PrP) peptides activates the mitochondrial-mediated apoptotic pathway. In cortical neurons, addition of the synthetic Abeta1-40 or PrP106-126 peptides depletes ER Ca2+ content, leading to cytosolic Ca2+ overload. The Ca2+ released through ryanodine (RyR) and inositol 1,4,5-trisphosphate (IP3R) receptors was shown to be involved in the loss of mitochondrial membrane potential, Bax translocation to mitochondria and apoptotic death. Our data further demonstrate that Ca2+ released from the ER leads to the depletion of endogenous GSH levels and accumulation of reactive oxygen species, which were also involved in the depolarization of the mitochondrial membrane. These results illustrate that the early Abeta- and PrP -induced perturbation of ER Ca2+ homeostasis affects mitochondrial function, activating the mitochondrial-mediated apoptotic pathway and help to clarify the mechanism implicated in neuronal death that occurs in AD and PrD.

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Available from: Elisabete Baptista Ferreiro,
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    • "When the UPR has clearly been initiated, as made obvious by the increased expression of many marker proteins, but its restorative measures are insufficient to save the cell, then Ca 2 þ dynamics between the ER/SR and mitochondria come into play. In this scenario , the ER/SR releases a significant amount of Ca 2 þ that is then taken up by the mitochondria (Deniaud et al., 2008; Ferreiro et al., 2008; Szegezdi et al., 2006). This process leads to the initiation of apoptosis in cells that cannot recover from the degree of stress to which they have been exposed. "
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    • "c o m / l o c a t e / b b a d i s the brain of transgenic AD mice before plaque deposition [68], suggesting that oxidative damage occurs in early stages of the disease and that progression to AD might be related to depletion of antioxidant defenses. Aβ was also demonstrated to induce oxidative stress in cultured hippocampal and cortical neurons [20] [29]. There are evidences for modifications in transcription factors related with mitochondrial biogenesis and antioxidant defenses in AD [11]. "
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    • "Recently, it was shown that presenilin-1 and -2, components of the g-secretase complex, are enriched in the MAMs (Area-Gomez et al., 2009) and that mutations in presenilin-1 and -2 upregulate MAM function and increase ER-mitochondria connectivity (Area-Gomez et al., 2012). We have previously shown in cortical neurons that Ab 1e40 , in a fibrillar state, induces the release of ER Ca 2þ through IP 3 R and RyR channels (Ferreiro et al., 2004), which is implicated in mitochondrial depolarization, release of cytochrome c, translocation of Bax to mitochondria, and apoptosis (Ferreiro et al., 2006, 2008). Our results largely suggest that the potentiation of mitCa 2þ retention that occurs in cells exposed to Ab þ NMDA is related to ER-mitochondria crosstalk. "
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