Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects

Topic: Brain proteins, microglia and lab models

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.

Key findings

• 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.

Why it matters

In mice, nuclear loss of TDP-43 in brain endothelial cells disrupted the blood-brain barrier and caused hallmarks of frontotemporal dementia including fibrin deposition, gliosis, phospho-Tau accumulation, and impaired memory and social interaction. These data show a mechanism by which TDP-43 mutation may contribute to ALS-FTD, based on animal models.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1126/sciadv.ads0505
• PubMed: 40238886
• Original source →
• Free full text: Science Advances →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{ashok2025-40238886,
  author  = {Ashok, Cheemala and Kimble, Amy L. and Burrage, Emily Nicole and Helming, Stephen B. and Tyburski, Jordan D. and Leclair, Nathan K. and Omar, Omar M. and Zuberi, Aamir R. and others},
  title   = {{Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects}},
  journal = {Science Advances},
  year    = {2025},
  doi     = {10.1126/sciadv.ads0505},
  pmid    = {40238886},
  url     = {https://doi.org/10.1126/sciadv.ads0505}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A Nature · 2022-02-23 · usefulness score 64/100 · Lewy body dementia
• TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A Nature · 2022-02-23 · usefulness score 64/100 · Lewy body dementia
• Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration Nature neuroscience · 2019-01-14 · usefulness score 62/100 · Lewy body dementia
• TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD Nature neuroscience · 2018-01-08 · usefulness score 61/100 · Lewy body dementia
• TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD Science (New York, N.Y.) · 2015-08-01 · usefulness score 57/100 · Lewy body dementia
• Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders Nature reviews. Neurology · 2018-01-29 · usefulness score 56/100 · Brain scans and imaging
• TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD Nature neuroscience · 2018-03-19 · usefulness score 56/100 · Brain tissue and pathology
• Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy Proceedings of the National Academy of Sciences of the United States of America · 2013-02-11 · usefulness score 51/100 · Lewy body dementia
• Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation Nature reviews. Neuroscience · 2021-03-02 · usefulness score 49/100 · Brain tissue and pathology

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• Novel approaches for the treatment of frontotemporal dementia: is there hope for the future? Expert Review of Neurotherapeutics · 2025-08-13 · usefulness score 38/100 · Lewy body dementia

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