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: 4.85). 06/2011; 33(4):824.e5-16. DOI: 10.1016/j.neurobiolaging.2011.04.011
Source: PubMed

ABSTRACT 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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    • "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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    • "Moreover, cerebrovascular accumulation of Aβ in mice was shown to induce apoptotic cell death in ECs [8]. In our previous studies, we demonstrated the involvement of ER Ca 2+ release induced by different Aβ peptides in mitochondria-mediated apoptosis in cortical neurons and AD cybrids [28] [38] [70]. Thapsigarginmediated perturbation in Ca 2+ homeostasis was shown to lead to apoptosis in a cross-talk between the death receptor and mitochondrial pathways [71]. "
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    ABSTRACT: Neurovascular dysfunction arising from endothelial cell damage is an early pathogenic event that contributes to the neurodegenerative process occurring in Alzheimer's disease (AD). Since the mechanisms underlying endothelial dysfunction are not fully elucidated, this study was aimed to explore the hypothesis that brain endothelial cell death is induced upon the sustained activation of the endoplasmic reticulum (ER) stress response by amyloid-beta (Aβ) peptide, which deposits in the cerebral vessels in many AD patients and transgenic mice. Incubation of rat brain endothelial cells (RBE4 cell line) with Aβ1-40 increased the levels of several markers of ER stress-induced unfolded protein response (UPR), in a time-dependent manner, and affected the Ca(2+) homeostasis due to the release of Ca(2+) from this intracellular store. Finally, Aβ1-40 was shown to activate both mitochondria-dependent and -independent apoptotic cell death pathways. Enhanced release of cytochrome c from mitochondria and activation of the downstream caspase-9 were observed in cells treated with Aβ1-40 concomitantly with caspase-12 activation. Furthermore, Aβ1-40 activated the apoptosis effectors' caspase-3 and promoted the translocation of apoptosis-inducing factor (AIF) to the nucleus demonstrating the involvement of caspase-dependent and -independent mechanisms during Aβ-induced endothelial cell death. In conclusion, our data demonstrate that ER stress plays a significant role in Aβ1-40-induced apoptotic cell death in brain endothelial cells suggesting that ER stress-targeted therapeutic strategies might be useful in AD to counteract vascular defects and ultimately neurodegeneration.
    Biochimica et Biophysica Acta 08/2013; DOI:10.1016/j.bbadis.2013.08.007 · 4.66 Impact Factor
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    • "Aging, the major risk factor in developing AD, is associated with declines in mitochondrial function in the central nervous system (Bowling et al., 1993; Hauptmann et al., 2009; Hong et al., 2008; Ross et al., 2010; Yao et al., 2009). Moreover, the cybrid model of AD, in which mtDNA from AD patients' platelets was transferred into cells lacking mtDNA, showed decreased mitochondrial mobility, increased oxidative stress, decreased cytochrome oxidase activity, and decreased mitochondrial membrane potential, suggesting that mitochondria and mtDNA abnormalities contribute to AD pathogenesis (Costa et al., 2012; Swerdlow, 2007). "
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    ABSTRACT: Mitochondrial DNA (mtDNA) damage and the generation of reactive oxygen species have been associated with and implicated in the development and progression of Alzheimer's disease. To study how mtDNA damage affects reactive oxygen species and amyloid beta (Aβ) pathology in vivo, we generated an Alzheimer's disease mouse model expressing an inducible mitochondrial-targeted endonuclease (Mito-PstI) in the central nervous system. Mito-PstI cleaves mtDNA causing mostly an mtDNA depletion, which leads to a partial oxidative phosphorylation defect when expressed during a short period in adulthood. We found that a mild mitochondrial dysfunction in adult neurons did not exacerbate Aβ accumulation and decreased plaque pathology. Mito-PstI expression altered the cleavage pathway of amyloid precursor protein without increasing oxidative stress in the brain. These data suggest that mtDNA damage is not a primary cause of Aβ accumulation.
    Neurobiology of aging 05/2013; 34(10). DOI:10.1016/j.neurobiolaging.2013.04.014 · 4.85 Impact Factor
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