TDP-43 depletion disrupts blood brain barrier in neurodegeneration

Capillary epithelial cells within the blood brain barrier (BBB) breakdown in neurodegenerative disorders. A loss of a DNA binding protein called TDP-43 is thought to be the reason for blood-brain barrier breakdown. ECs and microglia are usually underrepresented in single nuclei analysis of the brain, so ERG transcription factor was stained to enrich them and sort them based on ERG subtype. Three clusters of ECs were identified: aging, degenerative and healthy. The degenerative group showed downregulation of β-catenin and upregulation of TNF/NF-kB with a loss of TDP-43. Capillary ECs were further separated into five clusters based on the top genes expressed within a cluster. Reactive clusters (REV1) were enriched degenerative ECs and homeostatic clusters (HC) were enriched normal ECs. REV1 had increased TNF/NF-kB signaling and decreased Wnt/ β-catenin compared to the HCs.Researchers also saw capillary ECs switching to a proinflammatory subtype during disease, which is thought to contribute to the breakdown of the BBB seen in neurodegenerative diseases. They used Uniform Manifold Approximation and Projection (UMAP) visualization which showed a clear increase in nuclear β-catenin in the HC cluster. Additionally, β-catenin transcriptional targets, such as TCF/LEF1, ABCG2, and APCDD1, were significantly upregulated in the HC cluster compared to REV1. These findings suggest that the REV1 population exhibits reduced nuclear β-catenin, lower TDP-43 levels, and diminished expression of Wnt signaling genes. NF-kB and Wnt function to maintain the BBB in the presence of TDP-43 and so it is theorized that a loss of TDP-43 shifts NF-kB to its proinflammatory functions causing the BBB to breakdown.

 

 

Reference:

Omar, O.M.F., Kimble, A.L., Cheemala, A. et al. Endothelial TDP-43 depletion disrupts core blood–brain barrier pathways in neurodegeneration. Nat Neurosci (2025).