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Fibronectin is a Proximal Mediator of APOE-ε4-induced Blood-Brain Barrier Dysfunction in Alzheimer’s Disease

EVENT: 
Weekly Seminar | Not Open to the Public
Who Should Attend: 
Researchers
Event Flyer: 
PDF icon kizil_6-24-25.pdf

Speakers

Associate Professor
Columbia University Irving Medical Center, NY, NY

Abstract

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, in part by driving early blood-brain barrier (BBB) breakdown, perivascular inflammation, and pathological extracellular matrix (ECM) remodeling. Excessive fibronectin deposition at the BBB basement membrane impairs endothelial–astrocyte crosstalk, disrupts tight junctions, and amplifies neuroinflammation, thereby accelerating cognitive decline in APOE-ε4 carriers. Through whole-genome sequencing of >10,000 APOE-ε4 homozygotes, we identified two rare FN1 variants that segregate exclusively with cognitively resilient individuals. Functional studies in iPSC-derived astrocyte– endothelial co-cultures and orthologous zebrafish models demonstrate that one genetic variant reduces pathogenic fibronectin fibrillogenesis at the BBB, restores tight-junction integrity, normalizes VEGFA signaling, and attenuates immune cell recruitment. Multi-omic profiling further reveals that FN1 variant remodels the vascular lipidome and transcriptome toward a homeostatic, anti-inflammatory state, providing mechanistic insight into variant-driven resilience. By pinpointing fibronectin as a proximal effector of APOE-ε4–induced BBB pathology, these findings establish FN1 as a tractable target for therapeutic intervention. In this presentation, I will discuss our genetic and mechanistic dissection of fibronectin’s role in BBB health, outline how naturally protective FN1 variants confer resilience in APOE-ε4 carriers, and highlight the therapeutic potential of targeting fibronectin–integrin interactions to preserve vascular integrity and prevent cognitive decline in Alzheimer’s disease.

Publications

Prabesh Bhattarai, Elanur Yilmaz, Elif Öykü Cakir, Hande Yüceer Korkmaz, Annie J. Lee, Yiyi Ma, Hilal Celikkaya, Mehmet Ilyas Cosacak, Verena Haage, Xue Wang, Nastasia Nelson, Weilin Lin, Yixin Zhang, Tal Nuriel, Dörthe Jülich, Özkan Iş, Scott A. Holley, Philip de Jager, Elizabeth Fisher, Kate Tubbesing, Andrew F. Teich, Taylor Bertucci, Sally Temple, Nilüfer Ertekin-Taner, Badri N. Vardarajan, Richard Mayeux, Caghan Kizil
APOE-ε4-induced Fibronectin at the blood-brain barrier is a conserved pathological mediator of disrupted astrocyte-endothelia interaction in Alzheimer’s disease
bioRxiv
Prabesh Bhattarai, Tamil Iniyan Gunasekaran, Michael E. Belloy, Dolly Reyes-Dumeyer, Dörthe Jülich, Hüseyin Tayran, Elanur Yilmaz, Delaney Flaherty, Bengisu Turgutalp, Gauthaman Sukumar, Camille Alba, Elisa Martinez McGrath, Daniel N. Hupalo, Dagmar Bacikova, Yann Le Guen, Rafael Lantigua, Martin Medrano, Diones Rivera, Patricia Recio, Tal Nuriel, Nilüfer Ertekin-Taner, Andrew F. Teich, Dennis W. Dickson, Scott Holley, Badri N. Vardarajan
Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s disease
Acta Neuropathol
Tayran H, Yilmaz E, Bhattarai P, Min Y, Wang X, Ma Y, Wang N, Jeong I, Nelson N, Kassara N, Cosacak MI, Dogru RM, Reyes-Dumeyer D, Stenersen JM, Reddy JS, Qiao M, Flaherty D, Gunasekaran TI, Yang Z, Jurisch-Yaksi N, Teich AF, Kanekiyo T, Tosto G, Vardarajan BN, İş Ö, Ertekin-Taner N, Mayeux R, Kizil C
ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer’s disease through BDNF/NGFR signaling
Cell Genom

When

Tuesday, June 24, 2025 - 12:30pm

Where

Conference Room: 
Billings Building – Rosedale

More Information

Darlene White