Amyloid β-induced ER stress is enhanced under mitochondrial dysfunction conditions

Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Neurobiology of aging (Impact Factor: 5.01). 06/2011; 33(4):824.e5-16. DOI: 10.1016/j.neurobiolaging.2011.04.011
Source: PubMed


Previously we reported that endoplasmic reticulum (ER)-mitochondria crosstalk is involved in amyloid-β (Aβ)-induced apoptosis. Now we show that mitochondrial dysfunction affects the ER stress response triggered by Aβ using cybrids that recreate the defect in mitochondrial cytochrome c oxidase (COX) activity detected in platelets from Alzheimer's disease (AD) patients. AD and control cybrids were treated with Aβ or classical ER stressors and the ER stress-mediated apoptotic cell death pathway was accessed. Upon treatment, we found increased glucose-regulated protein 78 (GRP78) levels and caspase-4 activation (ER stress markers) which were more pronounced in AD cybrids. Treated AD cybrids also exhibited decreased cell survival as well as increased caspase-3-like activity, poli-ADP-ribose-polymerase (PARP) levels and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells. Finally, we showed that Aβ-induced caspase-3 activation in both cybrid cell lines was prevented by dantrolene, thus implicating ER Ca(2+) release in ER stress-mediated apoptosis. Our results demonstrate that mitochondrial dysfunction occurring in AD patients due to COX inhibition potentiates cell susceptibility to Aβ-induced ER stress. This study further supports the close communication between ER and mitochondria during apoptosis in AD.

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    • "Simultaneously, we found out that Aβ25-35 is able to induce mitochondrial dysfunction (Costa et al., 2012) as determined by its ability to increase ROS accumulation, whereas di-O-demethylcurcumin has the ability to reverse these events. A large number of experiments have demonstrated that Aβ25-35 plays an important role in cell apoptosis mediated by mitochondrial death pathway and ER stress pathway (Alberdi et al., 2013; Costa et al., 2012; Takuma et al., 2005). It is well known that Aβ25-35 induces mitochondria dysfunction by increasing the intracellular ROS production (Shearman et al., 1994), depolarizing the mitochondrial membrane, opening the mitochondrial permeability transition pore (MPTP), and inducing the release of cytochrome c, which, in turn, activates caspase-3 protein which plays an important role in cell apoptosis (Budihardjo et al., 1999; Manczak et al., 2010; Zhang and Armstrong, 2007). "
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    ABSTRACT: Amyloid-β peptides (Aβ), a major component of senile plaques, play an important role in the development and progression of Alzheimer's disease. Several lines of evidence have demonstrated that Aβ-induced neuronal death is mediated by oxidative stress. The present study aimed to evaluate the potential involvement of di-O-demethylcurcumin, an analog of curcuminoid, on Aβ-induced neurotoxicity in culture neuroblastoma cells (SK-N-SH cells) through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and the suppression of nuclear factor-κB (NF-κB) signaling pathway and their downstream targets. The results showed that pretreatment with di-O-demethylcurcumin elevated cell viability and decreased the level of reactive oxygen species. Moreover, treatment with di-O-demethylcurcumin promoted the translocation of Nrf2 protein from the cytoplasm to the nucleus, increased the expression of Nrf2-ARE pathway-related downstream proteins including heme oxygenase (HO-1), NAD(P)H:quinone oxidoreductase 1 and glutamate-cysteine ligase catalytic subunit, and increased the activity of superoxide dismutase enzymes. On the other hand, di-O-demethylcurcumin suppressed the degradation of IκBα, translocation of the p65 subunit of NF-κB from cytoplasm to nucleus and thereby, attenuated the expression of inducible nitric oxide synthase protein and nitric oxide production. Taken together, these results suggest that neuroinflammatory effect of di-O-demethylcurcumin might potentially be due to inhibit NF-κB and activate Nrf2 signaling pathways induced by Aβ25-35.
    Neurotoxicity Research 09/2015; DOI:10.1007/s12640-015-9558-4 · 3.54 Impact Factor
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    • "Under these conditions, ER may be a source of oxidative stress [34]. Several studies established a correlation between abnormal ER function and AD progression [36] [72] and Aβ has been shown to induce ER stress both in vitro and in vivo, subsequently leading to apoptotic cell death [16] [30] [80]. Furthermore, ER dysfunction can partially account for the perturbation of Ca 2+ i homeostasis reported in AD patient's brain and peripheral cells [49]. "
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    ABSTRACT: Oxidative stress and endoplasmic reticulum (ER) stress have been associated with Alzheimer's disease (AD) progression. In this study we analyzed whether oxidative stress involving changes in Nrf2 and ER stress may constitute early events in AD pathogenesis by using human peripheral blood cells and an AD transgenic mouse model at different disease stages. Increased oxidative stress and increased phosphorylated Nrf2 (p(Ser40)Nrf2) were observed in human peripheral blood mononuclear cells (PBMCs) isolated from individuals with mild cognitive impairment (MCI). Moreover, we observed impaired ER Ca(2+) homeostasis and increased ER stress markers in PBMCs from MCI individuals and mild AD patients. Evidence of early oxidative stress defense mechanisms in AD was substantiated by increased p(Ser40)Nrf2 in 3 month-old 3xTg-AD male mice PBMCs, and also with increased nuclear Nrf2 levels in brain cortex. However, SOD1 protein levels were decreased in human MCI PBMCs and in 3xTg-AD mice brain cortex; the latter further correlated with reduced SOD1 mRNA levels. Increased ER stress was also detected in the brain cortex of young female and old male 3xTg-AD mice. We demonstrate oxidative stress and early Nrf2 activation in AD human and mouse models, which fails to regulate some of its targets, leading to repressed expression of antioxidant defenses (e.g. SOD-1), and extending to ER stress. Results suggest markers of prodromal AD linked to oxidative stress associated with Nrf2 activation and ER stress that may be followed in human peripheral blood mononuclear cells. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 04/2015; 1852(7). DOI:10.1016/j.bbadis.2015.03.015 · 4.66 Impact Factor
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    • "Interestingly, the use of the microtubule stabilizer taxol reduced mitochondrial and cytosolic Aβ levels [60] showing that Aβ can be degraded by macroautophagy. Since ER stress triggered by Aβ 1–40 or thapsigargin induces mitochondria dysfunction through ER-to-mitochondria Ca 2+ transfer [61] [62] [63] [64], we can hypothesize that ER stress can cause microtubule disruption and subsequently affects autophagy flux. The 26S proteasome is involved in the formation and restructuration of microtubules [65]. "
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    ABSTRACT: Abnormal accumulation of amyloid-β (Aβ) peptide in the brain is a pathological hallmark of Alzheimer's disease (AD). In addition to neurotoxic effects, Aβ also damages brain endothelial cells (ECs) and may thus contribute to the degeneration of cerebral vasculature, which has been proposed as an early pathogenic event in the course of AD and is able to trigger and/or potentiate the neurodegenerative process and cognitive decline. However, the mechanisms underlying Aβ-induced endothelial dysfunction are not completely understood. Here we hypothesized that Aβ impairs protein quality control mechanisms both in the secretory pathway and in the cytosol in brain ECs, leading cells to death. In rat brain RBE4 cells, we demonstrated that Aβ1-40 induces the failure of the ER stress-adaptive unfolded protein response (UPR), deregulates the ubiquitin-proteasome system (UPS) decreasing overall proteasome activity with accumulation of ubiquitinated proteins and impairs the autophagic protein degradation pathway due to failure in the autophagic flux, which culminates in cell demise. In conclusion, Aβ deregulates proteostasis in brain ECs and, as a consequence, these cells die by apoptosis.
    Biochimica et Biophysica Acta 02/2014; 1843(6). DOI:10.1016/j.bbamcr.2014.02.016 · 4.66 Impact Factor
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