PREreviews of Inflammatory reprogramming of human brain endothelial cells compromises blood–brain barrier integrity in Alzheimer’s disease

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Inflammatory reprogramming of human brain endothelial cells compromises blood–brain barrier integrity in Alzheimer’s disease

by Rebecca L. Pinals, Md Rezaul Islam, Oisín King, Aaron Choi, Eulim Kang, Masayuki Nakano, Anjanet Tuyéras, Maeesha Tasnim Naomi, Arthur Ngo, Alan Jiang, Nhat Truong, Emre Agbas, Claudia F. Lozano Cruz, Colin Staab, Tak Ko, David A. Bennett, Alice E. Stanton, Robert Langer, and Li-Huei Tsai

Posted: September 28, 2025
Server: bioRxiv
DOI: 10.1101/2025.09.26.678918

Abstract

Summary

Blood-brain barrier (BBB) dysfunction is an early feature of Alzheimer’s disease (AD), yet the endothelial gene-regulatory programs involved remain incompletely understood. We integrate postmortem human single-nucleus transcriptomics with iPSC-based BBB models to define a conserved, inflammation-driven pathway that compromises barrier integrity. We identify an NF-κB-associated endothelial gene module endoM2 that is elevated in AD, inversely correlated with cognition, and enriched for inflammation and endothelial-to-mesenchymal transition signatures. Cytokine stimulation of iPSC-derived brain endothelial cells induces morphological remodeling, lipid accumulation, junctional disruption, and transcriptomic shifts that mirror endoM2. A targeted drug screen identifies the NF-κB inhibitor BAY11-7082 as protective against cytokine-induced changes. In our perfusable iPSC-derived BBB-Chip that recapitulates human BBB signatures, single-cell profiling reveals inflammatory endothelial state-specific programs reflecting those in AD brains and demonstrates that BAY11-7082 suppresses cytokine-triggered dysfunction and reverses inflammation-associated gene activation. Together, these findings position cerebrovascular inflammation as a therapeutic target to preserve BBB integrity in AD.

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PREreview by Domenico Azarnia Tehran et al. of PhD Program in Biomedical Sciences, University of Padua

Authored by Domenico Azarnia Tehran, Valentina Masola, Anna Guazzo, Michele Di Palma, Roberta Frison, Eloisa Turco, Michela Carraro, Emy Basso, Martina Quagliata, Annarita Zanon, Elena Baldisseri, Martina Esposito, Federica Boscolo Nata, GIORGIA PALLAFACCHINA, ANNAMARIA LIA, VALERIA SCALCON, Emanuela Beretta, Andressa Brancher Roeder, Giulia Rocca, and 14 other authors of PhD Program in Biomedical Sciences, University of Padua

The review is the result of a collaborative live review discussion held on October 28th, 2025, organized and hosted by the PhD school in Biomedical Sciences of the University of Padova as part of the Journal Club activity. The discussion was followed by additional asynchronous work by students and…

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