Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects
Year: 2025
Type: article
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.
Source: Science Advances
Institutions: University of Connecticut, UConn Health, Jackson Laboratory
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,500
Awards: Inhibition of BACE1 for benefiting Alzheimer's patients, G2408687097, G278894908, Contributions of Endothelial RNA-binding Protein Dysregulation to Blood Brain Barrier Defects and Neurodegenerative Disease, G2962577771, G3217277979, G3797204848, BACE1 in neurodegeneration and neurological dysfunction, G439175044, Investigation of alternative splicing in response to low and disturbed flow, G9000082290
OpenAlex ID: W4409493849