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

Alzheimer's & dementia : the journal of the Alzheimer's Association 2024 Mar

filter terms:

Genome-wide association studies link susceptibility to late-onset Alzheimer's disease (LOAD) with EphA1. Sequencing identified a non-synonymous substitution P460L as a LOAD risk variant. Other Ephs regulate vascular permeability and immune cell recruitment. We hypothesized that P460L dysregulates EphA1 receptor activity and impacts neuroinflammation. EphA1/P460L receptor activity was assayed in isogenic Human Embryonic Kidney (HEK) cells. Soluble EphA1/P460L (sEphA1/sP460L) reverse signaling in brain endothelial cells was assessed by T-cell recruitment and barrier function assays. EphA1 and P460L were expressed in HEK cells, but membrane and soluble P460L were significantly reduced. Ligand engagement induced Y781 phosphorylation of EphA1 but not P460L. sEphA1 primed brain endothelial cells for increased T-cell recruitment; however, sP460L was less effective. sEphA1 decreased the integrity of the brain endothelial barrier, while sP460L had no effect. These findings suggest that P460L alters EphA1-dependent forward and reverse signaling, which may impact blood-brain barrier function in LOAD. EphA1-dependent reverse signaling controls recruitment of T cells by brain endothelial cells. EphA1-dependent reverse signaling remodels brain endothelial cell contacts. LOAD-associated P460L variant of EphA1 shows reduced membrane expression and reduced ligand responses. LOAD-associated P460L variant of EphA1 fails to reverse signal to brain endothelial cells. © 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

Citation

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. Alzheimer's disease-associated P460L variant of EphA1 dysregulates receptor activity and blood-brain barrier function. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2024 Mar;20(3):2016-2033