Alzheimer's disease‐associated P460L variant of EphA1 dysregulates receptor activity and blood‐brain barrier function

• DOI: 10.1002/alz.13603
• Publication Date: 2024-01-07T10:05:06Z
• Authors: Helen A. Owens; Lauren E. Thorburn; Elisabeth Walsby; Owen R. Moon; Pierre Rizkallah; Subuhi Sherwani; Caroline L. Tinsley; Louise Rogers; Camilla Cerutti; Anne J. Ridley; Julie Williams; Vera Knäuper; Ann Ager
• Keywords: HEK 293 cells

Abstract INTRODUCTION Genome‐wide association studies link susceptibility to late‐onset Alzheimer's disease (LOAD) with EphA 1. Sequencing identified a non‐synonymous substitution P460L as LOAD risk variant. Other Ephs regulate vascular permeability and immune cell recruitment. We hypothesized that dysregulates EphA1 receptor activity impacts neuroinflammation. METHODS EphA1/P460L was assayed in isogenic Human Embryonic Kidney (HEK) cells. Soluble (sEphA1/sP460L) reverse signaling brain endothelial cells assessed by T‐cell recruitment barrier function assays. RESULTS were expressed HEK cells, but membrane soluble significantly reduced. Ligand engagement induced Y781 phosphorylation of not P460L. sEphA1 primed for increased recruitment; however, sP460L less effective. decreased the integrity barrier, while had no effect. DISCUSSION These findings suggest alters EphA1‐dependent forward signaling, which may impact blood‐brain LOAD. Highlights controls T remodels contacts. LOAD‐associated variant shows reduced expression ligand responses. fails signal