Oxidative stress triggers-the amyloidogenic pathway in human vascular smooth muscle cells

Cerebral amyloid angiopathy, associated to most cases of Alzheimer's disease (AD), is characterized by the deposition of amyloid beta-peptide (AB) 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 B-protein precursor (APP) cleavage and produce A beta(1-40) and A beta(1-42). Oxidative stress, a key factor in the etiology and pathophysiology of AD, up-regulates beta-site APP cleaving enzyme 1 (BACE1) expression, as well as A beta(1-40) and A beta(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. (C) 2007 Elsevier Inc. All rights reserved.