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Keywords:

  • amyloid beta peptide;
  • cerebral amyloid angiopathy;
  • IL-1β;
  • inflammation;
  • PI3K;
  • de-differentiation and vascular smooth muscle cells

Summary

Several studies have shown that the accumulation of β-amyloid peptides in the brain parenchyma or vessel wall generates an inflammatory environment. Some even suggest that there is a cause-and-effect relationship between inflammation and the development of Alzheimer's disease and/or cerebral amyloid angiopathy (CAA). Here, we studied the ability of wild-type Aβ1-40-peptide (the main amyloid peptide that accumulates in the vessel wall in sporadic forms of CAA) to modulate the phenotypic transition of vascular smooth muscle cells (VSMCs) toward an inflammatory/de-differentiated state. We found that Aβ1-40-peptide alone neither induces an inflammatory response, nor decreases the expression of contractile markers; however, the inflammatory response of VSMCs exposed to Aβ1-40-peptide prior to the addition of the pro-inflammatory cytokine IL-1β is greatly intensified compared with IL-1β-treated VSMCs previously un-exposed to Aβ1-40-peptide. Similar conclusions could be drawn when tracking the decline of contractile markers. Furthermore, we found that the mechanism of this potentiation highly depends on an Aβ1-40 preactivation of the PI3Kinase and possibly NFκB pathway; indeed, blocking the activation of these pathways during Aβ1-40-peptide treatment completely suppressed the observed potentiation. Finally, strengthening the possible in vivo relevance of our findings, we evidenced that endothelial cells exposed to Aβ1-40-peptide generate an inflammatory context and have similar effects than the ones described with IL-1β. These results reinforce the idea that intraparietal amyloid deposits triggering adhesion molecules in endothelial cells, contribute to the transition of VSMCs to an inflammatory/de-differentiated phenotype. Therefore, we suggest that acute inflammatory episodes may increase vascular alterations and contribute to the ontogenesis of CAA.