Deregulation of CypA‐EMMPRIN pathway in chronic cerebral hypoperfusion: Implication in vascular dementia

Abstract

AbstractBackgroundChronic cerebral hypoperfusion (CCH) has been shown to be a key mechanism in vascular cognitive impairment and dementia, leading to various pathologies including blood brain barrier disruption, extracellular matrix dysfunction and inflammation. Cyclophilin A (CypA), an oxidative stress‐induced factor, is secreted into the extracellular space upon stimulation or during cell death and binds to the extracellular matrix metalloproteinase inducer (EMMPRIN). EMMPRIN may in turn activate matrix metalloproteinases (MMPs), leading to downstream inflammatory processes and vascular remodeling. While CypA and EMMPRIN have been studied in animal models of acute ischemic and hemorrhagic stroke [1‐4], their potential involvement in CCH as well as in the clinical setting of VaD awaits investigation.MethodIn the first part of the study, the bilateral common carotid artery stenosis (BCAS) model was utilised: microcoils were inserted in both the left and right common carotid arteries for 30 days to induce CCH in male C57BL/6J mice. Sham controls were operated in the same manner without the insertion of microcoils. At the 30‐days endpoint, the animals were euthanized; brain samples were collected and processed for CypA, EMMPRIN, MMP‐2 and MMP‐9 measurement using western blot. In the second part of the study, a cross‐sectional clinical study with 36 non‐cognitive impaired controls and 48 vascular dementia (VaD) subjects was performed. Blood samples were collected, and serum CypA, EMMPRIN, MMP‐2 and MMP‐9 levels were measured using sandwich ELISAs.ResultLower CypA and higher EMMPRIN levels were found in the brains of BCAS‐induced mice, and in the serum of VaD patients. While MMP‐2 was higher in BCAS‐inducted mice, MMP‐9 was higher in VaD patients. Interestingly in the clinical cohort, higher MMP‐2 was found in the presence of lacunes while MMP‐9 was higher in the presence of white matter hyperintensities, cortical infarct and lacunae, suggesting that the MMPs may be involved in differential pathways despite both being downstream of the CypA‐EMMPRIN pathway.ConclusionThe present study demonstrated that the deregulation of CypA, EMMPRIN and MMPs may play an important role during CCH, and thus be useful clinical biomarkers and potential therapeutic targets in VaD.