TDP-43's role in Alzheimer's disease: from accompanying protein to possible blood vessel problem

TAR DNA-binding protein 43 kDa (TDP-43) may act as a driver of neurovascular dysfunction in Alzheimer's disease (AD).

• TDP-43 aggregates in astrocytes and endothelial cells, impairing blood-brain barrier integrity and metabolic homeostasis.
• Loss of endothelial TDP-43 disrupts β-catenin signaling and fibronectin, leading to vascular breakdown and neuroinflammation.
• Astrocytic aggregates of TDP-43 are associated with reduced levels of aquaporin-4 and CD146, which further compromise clearance pathways.
• These mechanisms may accelerate the progression of AD and contribute to clinical variability and limited treatment responses in TDP-43-positive patients.
• Reclassifying TDP-43 as an upstream driver could facilitate the development of new biomarkers and precision therapies targeting neurovascular unit dysfunction.

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