PDGF-BB mitigates pericyte injury by activating the PHF19-PRC2 complex via the miR-221/BRCA1 signaling axis in Alzheimer's disease

Platelet-derived growth factor-BB (PDGF-BB) is a critical factor in maintaining pericyte function. Damage to pericytes has been shown to accelerate the progression of Alzheimer's disease (AD). This study aimed to investigate the role of PDGF-BB in the pathogenesis of AD. Pericytes were treated with Aβ1-42 alone or in combination with PDGF-BB. Cell viability, proliferation, and apoptosis were assessed using the CCK-8 assay, EdU assay, and flow cytometry, respectively. Co-immunoprecipitation was performed to investigate the interactions among BRCA1, PHF19, EZH2, EED, SUZ12, and RbAp46/48. The relationships among BRCA1, miR-221-3p, and miR-222-3p were evaluated using a luciferase reporter assay. APP/PS1 transgenic mice were administered PDGF-BB, and behavioral performance was assessed via the Morris water maze test. Immunofluorescence staining and Evans Blue assay were employed to examine pericyte coverage and blood-brain barrier (BBB) integrity. PDGF-BB enhanced cell viability and proliferation while inhibiting apoptosis in Aβ1-42-treated pericytes; these effects were reversed by BRCA1 overexpression. BRCA1 expression was upregulated in pericytes exposed to Aβ1-42. Furthermore, PDGF-BB treatment resulted in the downregulation of BRCA1 and the upregulation of members of the PHF19-PRC2 complex, including PHF19, EZH2, EED, SUZ12, and RbAp46/48. BRCA1 was found to interact with these PHF19-PRC2 complex components. Additionally, miR-221 suppressed BRCA1 expression by directly targeting BRCA1, whereas miR-222 interacted with BRCA1 without affecting its expression. In vivo, PDGF-BB administration improved learning and memory abilities, increased pericyte coverage, and enhanced blood-brain barrier integrity in an Alzheimer's disease mouse model. PDGF-BB activated PHF19-PRC2 complex through the regulation of the miR-221/BRCA1 axis, thereby decreasing blood-brain barrier permeability and improving learning and memory abilities in AD mouse models. Consequently, PDGF-BB may have a therapeutic potential in the progression of AD. • PDGF-BB restores blood-brain barrier integrity and mitigates pericyte loss in Alzheimer’s disease. • The miR-221/BRCA1 axis activates the PHF19-PRC2 complex to enhance pericyte function. • PDGF-BB improves cognitive function and vascular stability in Alzheimer’s disease mouse models.