Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects
Cheemala Ashok, Amy L. Kimble, Emily N. Burrage, Stephen B. Helming, Jordan D. Tyburski, Nathan K. Leclair, Omar M. Omar, Aamir Zuberi, Melissa Murphy, Evan R. Jellison, Bo Reese, Xiangyou Hu, Cathleen Lutz, Riqiang Yan, Patrick A. Murphy
Abstract
Mutations in the TARDBP gene encoding TDP-43 protein are linked to loss of function in neurons and familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We recently identified reduced nuclear TDP-43 in capillary endothelial cells (ECs) of donors with ALS-FTD. Because blood-brain barrier (BBB) permeability increases in ALS-FTD, we postulated that reduced nuclear TDP-43 in ECs might contribute. Here, we show that nuclear TDP-43 is reduced in ECs of mice with an ALS-FTD–associated mutation in TDP-43 ( Tardbp G348C ) and that this leads to cell-autonomous loss of junctional complexes and BBB integrity. Targeted excision of TDP-43 in brain ECs recapitulates BBB defects and loss of junctional complexes and ultimately leads to fibrin deposition, gliosis, phospho-Tau accumulation, and impaired memory and social interaction. Transcriptional changes in TDP-43–deficient ECs resemble diseased brain ECs. These data show that nuclear loss of TDP-43 in brain ECs disrupts the BBB and causes hallmarks of FTD.