Endothelial BACE1, regulating the endothelial-to-mesenchymal transition (EndMT) induced by particulate matter (PM), is associated with cerebrovascular disease: Involvement of endothelial BACE1 in BBB disruption caused by diabetes

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EndMT has emerged as a mechanism of vascular disease onset. Our previous study showed that PM exposure induces EndMT-associated cardiac fibrosis and BACE1-mediated brain endothelial dysfunction. Here we investigated whether BACE1 and EndMT are associated with PM-induced brain endothelial dysfunction and the development of cerebrovascular diseases. The human brain endothelial cells exposed to PM showed that EndMT was regulated by BACE1. The mRNA sequencing analysis revealed that BACE1 overexpression induced EndMT through diverse genes, including GDF15. We found that these BACE1 and GDF15 protein levels were increased in postmortem brain of cognitively impaired individuals with central nervous system (CNS) vasculopathy, vascular dementia (VD), compared with those without VD. In endothelial cells derived from patients with diabetes and db/db mouse brains, an upregulation of BACE1, GDF15, and EndMT-related phenotype was observed, compared with the control. We suggest that upregulation of BACE1 and GDF15 is involved in EndMT, which is responsible for BBB disruption induced by PM or diabetes, a high-risk factor for cerebrovascular disease. This may represent a molecular mechanism that contributes to the development of cerebrovascular disease, serving as a critical link connecting the PM to the onset and progression of VD.

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