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

INTRODUCTION 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 P46...

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Published in:Alzheimer's & dementia 2024-03, Vol.20 (3), p.2016-2033
Main Authors: Owens, Helen A., Thorburn, Lauren E., Walsby, Elisabeth, Moon, Owen R., Rizkallah, Pierre, Sherwani, Subuhi, Tinsley, Caroline L., Rogers, Louise, Cerutti, Camilla, Ridley, Anne J., Williams, Julie, Knäuper, Vera, Ager, Ann
Format: Article
Language:English
Subjects:
Age of onset
Alzheimer Disease - genetics
Alzheimer's disease
Barriers
Blood
Blood-Brain Barrier
Brain
Cells
Endothelial Cells
EphA1
Genome-Wide Association Study
Genomes
Genomics
Glycerol
Humans
Kinases
late‐onset Alzheimer's disease
Ligands
Morality
Phosphorylation
Proteins
Receptor, EphA1 - metabolism
Recruitment
Signaling
Susceptibility
T‐cell recruitment
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Summary:INTRODUCTION 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. METHODS 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. RESULTS 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. DISCUSSION These findings suggest that P460L alters EphA1‐dependent forward and reverse signaling, which may impact blood‐brain barrier function in LOAD. Highlights 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.
ISSN:1552-5260
1552-5279
1552-5279
DOI:10.1002/alz.13603