Ptpn20 preserves actin-dependent vesicular trafficking and amyloid-β clearance capacity in the choroid plexus

Accumulation of amyloid-β (Aβ) in Alzheimer’s disease reflects not only excessive production but also impaired clearance. The choroid plexus (ChP), which forms the blood–cerebrospinal fluid barrier, plays an important role in cerebrospinal fluid turnover and molecular elimination; however, the mechanisms that maintain epithelial integrity and vesicle-mediated transport remain poorly understood. Here we identify 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 establish Ptpn20 as an essential determinant of ChP epithelial homeostasis and highlight impaired actin-dependent vesicular trafficking as a contributor to reduced Aβ clearance.