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.

Abbreviations: Ab, antibody, Aß, amyloid ß-peptide, AD, Alzheimer's disease, ADAMs, a disintegrin and metalloproteases, APP, amyloid ß-protein precursor, BACE1, ß-site APP cleaving enzyme type 1, CAA, cerebral amyloid angiopathy, FBS, fetal bovine serum, HA-VSMC, human aortic vascular smooth muscle cells, HC-VSMC, human cerebral vascular smooth muscle cells, hPRT, hypoxanthine phosphoribosyltransferase, JNK, c-Jun N-terminal Kinase, MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, PS, presenilin, RT-PCR, reverse transcriptase-polymerase chain reaction, SAPK, stress-activated protein kinases

Keywords: Alzheimer's disease, Amyloid ß-peptide, BACE1, Vascular smooth muscle cells, Oxidative stress, C-JNK, p38 MAPK