title: Loss of proteostasis induced by amyloid beta peptide in brain endothelial cells.
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.
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal; Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Apartado 3046, 3001-401 Coimbra, Portugal.
authors.forename: Ana Catarina
authors.initials: AC
authors.lastname: Fonseca
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal.
authors.forename: Catarina R
authors.initials: CR
authors.lastname: Oliveira
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal.
authors.forename: Cláudia F
authors.initials: CF
authors.lastname: Pereira
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal. Electronic address: cardoso.sandra.m@gmail.com.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Cardoso
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D025801:Ubiquitin / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D008869:Microtubule-Associated Proteins; D025801:Ubiquitin; D020169:Caspases; D046988:Proteasome Endopeptidase Complex
keywords: Alzheimer's disease; Amyloid-beta; Apoptosis; Autophagy; Endoplasmic reticulum stress; Ubiquitin–proteasome system