PDGF-BB alleviates pericyte damage by the activation of the PHF19-PRC2 complex via the miR-221/BRCA1 axis in Alzheimer's disease

Background PDGF-BB is one of the important factors to maintain the function of pericytes. Pericyte damage accelerates the progression of Alzheimer's disease (AD). The role of PDGF-BB in AD was verified in this study. Methods Pericytes were treated with Aβ1-42 or combined with PDGF-BB. CCK-8 assay, EdU assay and flow cytometry examined cell viability, proliferation and apoptosis. Co-Immunoprecipitation verified the relationship among BRCA1, PHF19, EZH2, EED, SUZ12 and RbAp46/48.Luciferase reporter assay verified the relationship among BRCA1, miR-221-3p and miR-222-3p. APP/PS1 mice were administrated with PDGF-BB. Morris water maze test examined animal behaviors.Immunofluorescence staining and Evans Blue assay examined the pericyte coverage and blood brain barrier (BBB) integrity. Results PDGF-BB enhanced cell viability and proliferation, while inhibited apoptosis of Aβ1-42-treated pericytes, which was abrogated by BRCA1 overexpression. BRCA1 was up-regulated in Aβ1-42-treated pericytes. Additionally, PDGF-BB treatment caused a down-regulation of BRCA1 and up-regulation of PHF19-PRC2 complex members, PHF19, EZH2, EED, SUZ12 and RbAp46/48. BRCA1 interacted with PHF19-PRC2 complex members. MiR-221 repressed BRCA1 expression by targeting BRCA1. MiR-222 interacted with BRCA1 and had no influence on BRCA1 expression. In vivo , PDGF-BB treatment ameliorated learning and memory ability and elevated pericyte coverage and BBB integrity in AD mice. Conclusion PDGF-BB activated PHF19-PRC2 complex by regulating miR-221/BRCA1 axis, thereby reducing the permeability of BBB and ameliorating the learning and memory ability of AD mice. Thus, PDGF-BB may play a therapeutic role in AD development.