Oxidative stress involving changes in Nrf2 and ER stress in early stages of Alzheimer's disease
| Autor: | Isabel Santana, Catarina R. Oliveira, Gladys L. Caldeira, Ildete L. Ferreira, Sandra I. Mota, Inês Baldeiras, Liliana Letra, Ana Cristina Rego, Rui Costa, Carmela Padovano, Ana Catarina R.G. Fonseca, Catarina Cunha, Cláudia Pereira |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Genetically modified mouse medicine.medical_specialty NF-E2-Related Factor 2 Lymphocyte SOD1 medicine.disease_cause Peripheral blood mononuclear cell Mice Superoxide Dismutase-1 Alzheimer Disease Internal medicine Calcium homeostasis medicine Animals Humans Cognitive Dysfunction RNA Messenger Molecular Biology Cells Cultured Aged Aged 80 and over Cerebral Cortex Superoxide Dismutase business.industry Endoplasmic reticulum Mild cognitive impairment Alzheimer's disease Middle Aged Endoplasmic Reticulum Stress Mice Inbred C57BL Oxidative Stress Endocrinology medicine.anatomical_structure Unfolded protein response Molecular Medicine Female business Oxidative stress Homeostasis |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1852:1428-1441 |
| ISSN: | 0925-4439 |
| DOI: | 10.1016/j.bbadis.2015.03.015 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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