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

Owens, Helen A., Thorburn, Lauren M., Walsby, Elisabeth ORCID: https://orcid.org/0000-0001-8523-5017, Moon, Owen R., Rizkallah, Pierre ORCID: https://orcid.org/0000-0002-9290-0369, Sherwani, Subuhi, Tinsley, Caroline L., Rogers, Louise, Cerutti, Camilla, Ridley, Anne J., Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259, Knäuper, Vera ORCID: https://orcid.org/0000-0002-3965-9924 and Ager, Ann ORCID: https://orcid.org/0000-0002-5763-8908 2024. 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 20 (3) , pp. 2016-2033. 10.1002/alz.13603

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Dentistry Medicine
Publisher:	Wiley
ISSN:	1552-5260
Funders:	Neuroscience and Mental Health Research Institute, Sir Geraint Evans Cardiovascular Fund, UK Dementia Research Institute, School of Medicine, Cardiff University, School of Cellular and Molecular Medicine, University of Bristol, Leukemia Research Appeal for Wales, European Regional Development Fund, Ser Cymru II programme
Date of First Compliant Deposit:	21 November 2023
Date of Acceptance:	20 November 2023
Last Modified:	25 Oct 2024 01:13
URI:	https://orca.cardiff.ac.uk/id/eprint/164124

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