📣New preprint alert: Inflammatory reprogramming of brain endothelial cells impairs the blood–brain barrier in Alzheimer’s disease

Our latest preprint, “Inflammatory reprogramming of human brain endothelial cells compromises blood–brain barrier integrity in Alzheimer’s disease”, is now available on bioRxiv.

Background
The blood–brain barrier (BBB) is a specialized vascular interface that protects the brain by tightly regulating which molecules can pass from the blood into neural tissue. When the BBB is compromised, harmful substances, immune cells, and inflammatory signals can enter the brain, contributing to neurodegeneration. Growing evidence suggests that BBB dysfunction is an early and critical feature of Alzheimer’s disease (AD), but the gene-regulatory program(s) of this process in humans remain poorly understood.

Postmortem brain single-nucleus RNA-seq data from 431 participants of the ROSMAP cohorts were integrated. The conceptualization of the study, comprehensive data analyses and data visualisation led by Dr. Md Rezaul Islam, co-first and co-corresponding author, made critical observations in AD brains and generated hypotheses that were later tested/validated in a recently developed perfusable BBB model by Dr. Rebecca L. Pinals. Moreover, Dr. Islam identified inflammatory cell state–specific BBB signatures that are highly conserved in AD brains, providing proof-of-concept that inflammation plays a driving role in endothelial vulnerability and dysfunction. Importantly, these signatures could be rescued by an NF-κB inhibitor. Together, these findings position cerebrovascular inflammation as a therapeutic target to preserve BBB integrity in AD.

Major Findings

In this study, we integrated human postmortem single-nucleus transcriptomics with iPSC-based BBB models to uncover how cerebrovascular inflammation drives blood–brain barrier dysfunction in Alzheimer’s disease (AD). Here we

1. Identified an NF-κB–associated endothelial program (endoM2) elevated in AD, linked to amyloid/tau pathology, and inversely correlated with cognition.

2. Showed that inflammatory cytokine exposure reprograms brain endothelial cells toward AD-like states, marked by lipid accumulation, cell shape changes, and barrier disruption.

3. Extended these findings in a newly developed human perfusable BBB-Chip and demonstrated that the NF-κB inhibitor BAY11-7082 protects against cytokine-induced endothelial dysfunction and restores BBB integrity.

4. Identified inflammatory endothelial cell state–specific BBB scRNA-seq signatures that are highly conserved in AD brains, providing proof-of-concept that inflammation can drive endothelial vulnerability in AD

These findings position cerebrovascular inflammation as a therapeutic target for preserving BBB integrity in AD.

Summary

Overall, By linking genetic and environmental AD risk factors to endothelial reprogramming, this study uncovers a possible mechanism of BBB dysfunction and highlights endothelial plasticity as a potential therapeutic target.