Inhibition of β-catenin signaling by Amyloid-β in endothelial cells impairs vascular barrier integrity

Leasure, J. W.; Mai, T.; Fogel, A.; Danos, P.; Wang, L.; Sanborn, M. A.; Ye, Z.; Kim, Y.-M.; Wang, X.; Flores, J.; Mushtaq, M.; Toth, P. T.; Ong, S.-G.; Lazarov, O.; Rehman, J.

doi:10.1101/2024.11.05.622172

bioRxiv · 10.1101/2024.11.05.622172

Inhibition of β-catenin signaling by Amyloid-β in endothelial cells impairs vascular barrier integrity

Leasure, J. W.·Mai, T.·Fogel, A.·Danos, P.·Wang, L.·Sanborn, M. A.·Ye, Z.·Kim, Y.-M.·Wang, X.·Flores, J.·Mushtaq, M.·Toth, P. T.·Ong, S.-G.·Lazarov, O.·Rehman, J.

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Abstract

Dysfunction of the blood-brain barrier (BBB) is emerging as a critical mediator of Alzheimers Disease (AD) progression and precedes the formation of large Amyloid-{beta} (A{beta}) plaques in AD patients. Maintenance of the blood brain barrier integrity by brain microvascular endothelial cells (BMECs) is essential for brain homeostasis and is in part maintained by WNT/{beta}-catenin signaling. We hypothesized that A{beta} induces blood-brain barrier dysfunction by inhibiting WNT/{beta}- catenin signaling in brain endothelial cells, leading to reduced expression of BBB-related genes and barrier function. In brain endothelial cells, we found that A{beta} directly decreased {beta}-catenin transcriptional activity, but also inhibited activation of {beta}-catenin by the WNT3A peptide. Additionally, A{beta} reduced barrier integrity of ECs, which was in part restored by exposure to exogenous WNT3A. We observed A{beta}-induced inhibition within 3 hours of exposure. A{beta}-induced inhibition of {beta}-catenin signaling was consistent across both immortalized brain ECs and ECs differentiated from human induced pluripotent stem cells(iPSCs). We next investigated human iPSCs with and without the N141I mutation in presenilin-2 (PSEN2), known to increase A{beta} buildup and familial AD risk. We found the AD ECs showed smaller cell size and expressed lower VE-cadherin at the protein level. RNA sequencing revealed that the presence of PSEN2 N141I did not significantly impact gene expression of genes coding for proteins canonically involved in barrier integrity but did show differences in the expression of transposable elements. These results indicate that BBB dysfunction early in AD may be the result of A{beta} in the brain impairing WNT/{beta}-catenin signaling which maintains the barrier integrity of brain endothelial cells.

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Leasure, J. W., Mai, T., Fogel, A., Danos, P., Wang, L., Sanborn, M. A., Ye, Z., Kim, Y.-M., Wang, X., Flores, J., Mushtaq, M., Toth, P. T., Ong, S.-G., Lazarov, O., Rehman, J.. 2024-11-05. Inhibition of β-catenin signaling by Amyloid-β in endothelial cells impairs vascular barrier integrity. https://doi.org/10.1101/2024.11.05.622172

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