Ptpn20 regulates actin-dependent vesicular trafficking and amyloid-β clearance at the choroid plexus blood– CSF barrier

Clearance of amyloid-β (Aβ) across brain barrier interfaces is increasingly recognized as a key determinant of its accumulation in Alzheimer’s disease. The choroid plexus (ChP), forming the blood–CSF barrier, contributes to cerebrospinal fluid turnover and solute exchange, yet the molecular mechanisms regulating epithelial vesicular trafficking remain incompletely understood. Here we show that the cytoplasmic protein tyrosine phosphatase Ptpn20 as a key regulator of actin-dependent vesicular trafficking in ChP epithelial cells. Loss of Ptpn20 destabilizes apical F-actin architecture, suppresses both caveolae- and clathrin-mediated endocytosis, and reduces transcytosis of Aβ from the cerebrospinal fluid to the bloodstream. Transcriptomic profiling reveals coordinated downregulation of cytoskeletal, junctional, and vesicular transport modules. Mechanistically, Ptpn20 deficiency induces an early, transient hyperactivation of RhoA signaling that subsequently diminishes as actin architecture deteriorates, indicating biphasic uncoupling of RhoA–actin regulation. In the APP^NL-G-F knock-in background, loss of Ptpn20 exacerbates epithelial degeneration, apical Aβ accumulation, brain amyloid pathology, synaptic loss, and cognitive impairment. These findings suggest that preservation of choroid plexus epithelial integrity may represent a therapeutic strategy to enhance CSF-mediated waste clearance in neurodegenerative disease.