title: Oxidative stress involving changes in Nrf2 and ER stress in early stages of Alzheimer's disease.
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 Ca2+ 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 3month-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.
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Portugal.
authors: Sandra I
authors: SI
authors: Mota
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Portugal.
authors: Rui O
authors: RO
authors: Costa
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Portugal.
authors: Ildete L
authors: IL
authors: Ferreira
authors: Faculty of Medicine, University of Coimbra, Portugal; Neurology Unit of Coimbra University Hospital Center, Coimbra, Portugal.
authors: Isabel
authors: I
authors: Santana
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
authors: Gladys L
authors: GL
authors: Caldeira
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
authors: Carmela
authors: C
authors: Padovano
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
authors: Ana C
authors: AC
authors: Fonseca
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Portugal.
authors: Inês
authors: I
authors: Baldeiras
authors: Neurology Unit of Coimbra University Hospital Center, Coimbra, Portugal.
authors: Catarina
authors: C
authors: Cunha
authors: Neurology Unit of Coimbra University Hospital Center, Coimbra, Portugal.
authors: Liliana
authors: L
authors: Letra
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Portugal.
authors: Catarina R
authors: CR
authors: Oliveira
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Portugal. Electronic address: cpereira@fmed.uc.pt.
authors: Cláudia M F
authors: CM
authors: Pereira
authors: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Portugal. Electronic address: acrego@cnc.uc.pt.
authors: Ana Cristina
authors: AC
authors: Rego
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: Alzheimer's disease; Calcium homeostasis; Lymphocyte; Mild cognitive impairment; Oxidative stress; Peripheral blood mononuclear cell