2024-01-18 カーディフ大学
◆EphA1は脳のT細胞免疫応答に関与しており、P460L変異がこれを妨げ、脳内の炎症に影響を与え、遅発性アルツハイマー病のリスクを増加させる可能性があります。研究者は将来的な研究で、P460L変異がT細胞と血液脳関門に与える影響を詳細に調査し、アルツハイマー病治療における新しいアプローチを模索する意向です。
<関連情報>
- https://www.cardiff.ac.uk/news/view/2789187-new-links-between-late-onset-alzheimers-disease-and-the-immune-system
- https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13603
アルツハイマー病に関連するEphA1のP460L変異体、受容体活性と血液脳関門機能を調節する Alzheimer’s disease-associated P460L variant of EphA1 dysregulates receptor activity and blood-brain barrier function
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 & Dementia Published: 07 January 2024
DOI:https://doi.org/10.1002/alz.13603
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.
