title: Oxidative stress triggers the amyloidogenic pathway in human vascular smooth muscle cells.
abstract: Cerebral amyloid angiopathy, associated to most cases of Alzheimer's disease (AD), is characterized by the deposition of amyloid ss-peptide (Ass) in brain vessels, although the origin of the vascular amyloid deposits is still controversial: neuronal versus vascular. In the present work, we demonstrate that primary cultures of human cerebral vascular smooth muscle cells (HC-VSMCs) have all the secretases involved in amyloid ss-protein precursor (APP) cleavage and produce Ass(1-40) and Ass(1-42). Oxidative stress, a key factor in the etiology and pathophysiology of AD, up-regulates ss-site APP cleaving enzyme 1 (BACE1) expression, as well as Ass(1-40) and Ass(1-42) secretion in HC-VSMCs. This process is mediated by c-Jun N-terminal Kinase and p38 MAPK signaling and appears restricted to BACE1 regulation as no changes in the other secretases were observed. In conclusion, oxidative stress-mediated up-regulation of the amyloidogenic pathway in human cerebral vascular smooth muscle cells may contribute to the overall cerebrovascular amyloid angiopathy observed in AD patients.
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Coma
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Guix
authors.forename: Gerard
authors.initials: G
authors.lastname: Ill-Raga
authors.forename: Iris
authors.initials: I
authors.lastname: Uribesalgo
authors.forename: Francesc
authors.initials: F
authors.lastname: Alameda
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Valverde
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Muñoz
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D018384:Oxidative Stress; D015398:Signal Transduction
chemical_list: D016564:Amyloid beta-Protein Precursor