Down-regulation of platelet-derived growth factor receptor β in pericytes increases blood-brain barrier permeability and significantly enhances α-synuclein in a Parkinson's Disease 3D cell model in vitro under hyperglycemic condition.

Abstract

Background: Parkinson's Disease (PD) often presents with a compromised blood-brain barrier (BBB), which hyperglycemia may exacerbate. Pericytes, a key cell for BBB integrity, are potential therapeutic targets for neurodegenerative disorders. Few studies have developed 3D PD cell models incorporating neurovascular units (NVU) through the co-culture of human endothelial, pericytes, astrocytes, and SH-SY5Y cells to evaluate BBB impairment and the role of pericytes under hyperglycemic condition.

Method: A 3D PD like cell model was developed using 6-OHDA-affected SH-SY5Y cells, combined with endothelial cells, pericytes, and astrocytes through the Real Architecture for Tissue (RAFT) 3D co-culture system. PD incorporating reduced (30 % and 89 %) PDGFRβ NVU (RPN) with or without hyperglycemic model (HM) were also established. BBB permeability to sodium fluorescein was assessed, and BBB impairment was evaluated using BBB-associated proteins (ZO-1, CD54, CD144), cell-specific proteins (CD31, GFAP, PDGFRβ, CD13), tyrosine hydroxylase (TH), α-synuclein, oligomeric α-synuclein, and α-synuclein (ser9).

Results: PD 3D cell models incorporating RPN with or without hyperglycemia were successfully established in vitro. Graduately increased BBB impairment was observed in PD, PD with RPN, and PD with RPN combined with HM, indicated by decreased BBB-associated and cell-specific proteins, reduced TH, and increased α-synuclein, oligomeric α-synuclein, and α-synuclein (ser9) compared to the NVU model.

Conclusion: Reduced pericyte PDGFRβ could increase BBB permeability, accelerate PD progression, and exacerbate under hyperglycemic condition.