APOE-ε4-induced Fibronectin at the blood-brain barrier is a conserved pathological mediator of disrupted astrocyte-endothelia interaction in Alzheimer’s disease
Authors: Bhattarai Prabesh , Yilmaz Elanur , Cakir Elif Öykü , Korkmaz Hande Yüceer , Lee Annie J. , Ma Yiyi , Celikkaya Hilal , Cosacak Mehmet Ilyas , Haage Verena , Wang Xue , Nelson Nastasia , Lin Weilin , Zhang Yixin , Nuriel Tal , Jülich Dörthe , Iş Özkan , Holley Scott A. , de Jager Philip , Fisher Elizabeth , Tubbesing Kate , Teich Andrew F. , Bertucci Taylor , Temple Sally , Ertekin-Taner Nilüfer , Vardarajan Badri N. , Mayeux Richard , Kizil Caghan 
Published: January 2025

AbstractBlood-brain barrier (BBB) dysfunction is a key feature of Alzheimer’s disease (AD), particularly in individuals carrying theAPOE-ε4allele. This dysfunction worsens neuroinflammation and hinders the removal of toxic proteins, such as amyloid-beta (Aβ42), from the brain. In post-mortem brain tissues and in animal models, we previously reported that fibronectin accumulates at the BBB predominantly inAPOE-ε4carriers. Furthermore, we found a loss-of-function variant in the fibronectin 1 (FN1) gene significantly reduces aggregated fibronectin levels and decreases AD risk amongAPOE-ε4carriers. Yet, the molecular mechanisms downstream of fibronectin at the BBB remain unclear. The extracellular matrix (ECM) plays a crucial role in maintaining BBB homeostasis and orchestrating the interactions between BBB cell types, including endothelia and astrocytes. Understanding the mechanisms affecting the ECM and BBB cell types will be critical for developing effective therapies against AD, especially amongAPOE-ε4carriers. Here, we demonstrate thatAPOE-ε4, Aβ42, and inflammation drive the induction ofFN1expression in several models including zebrafish, mice, iPSC-derived human 3D astrocyte and 3D cerebrovascular cell cultures, and in human brains. Fibronectin accumulation disrupts astroglial-endothelial interactions and the signalling cascade between vascular endothelial growth factor (VEGF), heparin-binding epidermal growth factor (HBEGF) and Insulin-like growth factor 1 (IGF1). This accumulation of fibronectin inAPOE-ε4-associated AD potentiates BBB dysfunction, which strongly implicates reducing fibronectin deposition as a potential therapeutic target for AD.Graphical abstractAccessibility textThis image illustrates the effects of different APOE isoforms (ApoE-ε3 and ApoE-ε4) on blood-brain barrier (BBB) integrity, focusing on the molecular interactions between astrocytes and endothelial cells. This figure emphasizes the detrimental effects of ApoE-ε4 on BBB integrity via fibronectin accumulation and altered signaling pathways.Thetop sectionprovides a schematic overview of the blood-brain barrier, highlighting astrocytes, endothelial cells, and their interface.Theleft panelrepresents the ApoE-ε3 condition: Normal fibronectin (FN1) levels support healthy interactions between astrocytes and endothelial cells. Growth factors, including VEGFA, HBEGF, and IGF1, maintain BBB integrity through their respective receptors (VEGFR and EGFR). Green arrows indicate activation of these signaling pathways.Theright paneldepicts the ApoE-ε4 condition: Elevated fibronectin (FN1) disrupts astrocyte-endothelium interactions. FN1 binds integrins and activates focal adhesion kinase (FAK), inhibiting VEGFA, which is required for endothelial HBEGF that in turn activates IGF1 signaling. Red symbols indicate inhibition of HBEGF, VEGFA, and IGF1 pathways, leading to BBB dysfunction.HighlightsAPOE-ε4drives fibronectin deposition in Alzheimer’s, disrupting astrocyte-endothelia interactions.APOE-ε4and fibronectin co-localize, forming aggregates at blood-brain barrier (BBB).Fibronectin alters the signaling between VEGF, IGF1, and HBEGF impairing BBB function.Reducing fibronectin restores BBB integrity and offsetsAPOE-ε4pathology.