The unfolded protein response and proteostasis in Alzheimer disease

Amsterdam, The Netherlands.
Autophagy (Impact Factor: 11.75). 08/2011; 7(8):910-1. DOI: 10.4161/auto.7.8.15761
Source: PubMed

ABSTRACT Protein folding stress in the endoplasmic reticulum (ER) may lead to activation of the unfolded protein response (UPR), aimed to restore proteostasis in the ER. Previously, we demonstrated that UPR activation is an early event in Alzheimer disease (AD) brain. In our recent work we investigated whether activation of the UPR is employed to enhance the capacity of the ubiquitin proteasome system or autophagy in neuronal cells. We showed that the levels, composition and activity of the proteasome are not regulated by the UPR. In contrast, UPR activation enhances autophagy and LC3 levels are increased in neurons displaying UPR activation in AD brain. Our data suggest that autophagy is the major degradational pathway following UPR activation in neuronal cells and indicate a connection between UPR activation and autophagic pathology in AD brain.

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Available from: Wiep Scheper, Sep 27, 2015
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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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    • "As a matter of fact, UPR ER activation markers have been extensively documented in postmortem brain tissue from AD subjects and in animal and in vitro models of the disease (Hoozemans et al., 2009, 2012). Enhanced autophagy with the concomitant increase in LC3 levels was documented in AD neurons displaying UPR activation, pinpointing autophagy as a major degradative pathway upon UPR activation (Nijholt et al., 2011; Scheper et al., 2011). Moreover, it was observed that ER dysfunction and subsequent cell death triggered by Ab is correlated with the induction of autophagy (Lai et al., 2009). "
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    ABSTRACT: Autophagy is a housekeeping process responsible for the bulk degradation of misfolded protein aggregates and damaged organelles through the lysosomal machinery. Given its key role as a cellular quality control mechanism, autophagy is now a focus of intense scrutiny in Alzheimer's disease (AD). The hallmarks of this devastating neurodegenerative disease are the accumulation of misfolded amyloid-β (Aβ) peptide and hyperphosphorylated tau protein and neuronal loss, which are accompanied by mitochondrial dysfunction and endoplasmic reticulum (ER) stress, suggesting that faulty autophagy is a contributing factor to AD pathology. Indeed, the AD brain is characterized by a massive accumulation of autophagic vacuoles within large swellings along dystrophic neurites and defects at different steps of the autophagic-lysosomal pathway. In this sense, this review provides an overview on the role of autophagy on Aβ metabolism, tau processing and clearance, and the contribution of ER-phagy and mitophagy to AD pathology. From a therapeutic perspective, this review also intends to clarify whether, when, and how autophagy can be targeted to efficaciously counteract AD-related symptomatic and neuropathological features.
    DNA and Cell Biology 02/2015; 34(4). DOI:10.1089/dna.2014.2757 · 2.06 Impact Factor
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    • "Due to their highly reactive properties, ROS have a short half-life and limited diffusion distance [33], therefore, they usually inflict cellular damage and impact molecular pathways only near the site of their production [34]. It is well known that generation of ROS, sensitisation of ER and initiation of the unfolded protein response [35] and autophagy are closely related processes [36,37]. Taken together all the above information triggered our interest to explore the potential involvement of CYP2E1 in the regulation of ER stress. "
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    ABSTRACT: The cytochrome P450 (CYP) enzymes are a class of heme-containing enzymes involved in phase I metabolism of a large number of xenobiotics. The CYP family member CYP2E1 metabolises many xenobiotics and procarcinogens, it is not just expressed in the liver but also in many other tissues such as the kidney, the lung, the brain, the gastrointestinal tract and the breast tissue. It is induced in several pathological conditions including cancer, obesity, and type II diabetes implying that this enzyme is implicated in other biological processes beyond its role in phase I metabolism. Despite the detailed description of the role of CYP2E1 in the liver, its functions in other tissues have not been extensively studied. In this study we investigated the functional significance of CYP2E1 in breast carcinogenesis. Cellular levels of reactive oxygen species (ROS) were measured by H2DCFDA (2 2.9.2 2[prime],7[prime]-dichlorodihydrofluorescein diacetate ) staining and autophagy was assessed by tracing the cellular levels of autophagy markers using western blot assays. The endoplasmic reticulum stress and the unfolded protein response (UPR) were detected by luciferase assays reflecting the splicing of mRNA encoding the X-box binding protein 1 (XBP1) transcription factor and cell migration was evaluated using the scratch wound assay. Gene expression was recorded with standard transcription assays including luciferase reporter and chromatin immunoprecipitation. Ectopic expression of CYP2E1 induced ROS generation, affected autophagy, stimulated endoplasmic reticulum stress and inhibited migration in breast cancer cells with different metastatic potential and p53 status. Furthermore, evidence is presented indicating that CYP2E1 gene expression is under the transcriptional control of the p53 tumor suppressor. These results support the notion that CYP2E1 exerts an important role in mammary carcinogenesis, provide a potential link between ethanol metabolism and breast cancer and suggest that progression, and metastasis of advanced stages of breast cancer can be modulated by induction of CYP2E1 activity.
    Breast cancer research: BCR 11/2013; 15(6):R107. DOI:10.1186/bcr3574 · 5.49 Impact Factor
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