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Background  Cerebrovascular deposition of fibrillar amyloid β-protein (Aβ), a condition known as cerebral amyloid angiopathy (CAA), is a prominent pathological feature of Alzheimer's disease (AD) and related disorders. Accumulation of cerebral vascular fibrillar Aβ is implicated in promoting local neuroinflammation, causes marked degeneration of smooth muscle cells, and can lead to loss of vessel wall integrity with hemorrhage. However, the relationship between cerebral vascular fibrillar Aβ-induced inflammatory responses and localized cytotoxicity in the vessel wall remains unclear.  Steroidal-based anti-inflammatory agents, such as dexamethasone, have been reported to reduce neuroinflammation and hemorrhage associated with CAA. Nevertheless, the basis for the beneficial effects of steroidal anti-inflammatory drug treatment with respect to local inflammation and hemorrhage in CAA is unknown. The cultured human cerebrovascular smooth muscle (HCSM) cell system is a useful  in vitro  model to study the pathogenic effects of Aβ in CAA. To examine the possibility that dexamethasone may influence CAA-induced cellular pathology, we investigated the effect of this anti-inflammatory agent on inflammatory and cytotoxic responses to Aβ by HCSM cells.    Methods  Primary cultures of HCSM cells were treated with or without pathogenic Aβ in the presence or absence of the steroidal anti-inflammatory agent dexamethasone or the non-steroidal anti-inflammatory drugs indomethacin or ibuprofen. Cell viability was measured using a fluorescent live cell/dead cell assay. Quantitative immunoblotting was performed to determine the amount of cell surface Aβ and amyloid β-protein precursor (AβPP) accumulation and loss of vascular smooth cell α actin. To assess the extent of inflammation secreted interleukin-6 (IL-6) levels were measured by ELISA and active matrix metalloproteinase-2 (MMP-2) levels were evaluated by gelatin zymography.    Results  Pathogenic Aβ-induced HCSM cell death was markedly reduced by dexamethasone but was unaffected by ibuprofen or indomethacin. Dexamethasone had no effect on the initial pathogenic effects of Aβ including HCSM cell surface binding, cell surface fibril-like assembly, and accumulation of cell surface AβPP. However, later stage pathological consequences of Aβ treatment associated with inflammation and cell degeneration including increased levels of IL-6, activation of MMP-2, and loss of HCSM α actin were significantly diminished by dexamethasone but not by indomethacin or ibuprofen.    Conclusion  Our results suggest that although dexamethasone has no appreciable consequence on HCSM cell surface fibrillar Aβ accumulation it effectively reduces the subsequent pathologic responses including elevated levels of IL-6, MMP-2 activation, and depletion of HCSM α actin. Dexamethasone, unlike indomethacin or ibuprofen, may diminish these pathological processes that likely contribute to inflammation and loss of vessel wall integrity leading to hemorrhage in CAA.

Dexamethasone diminishes the pro-inflammatory and cytotoxic effects of amyloid β-protein in cerebrovascular smooth muscle cells