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Reframing TDP‐43 in Alzheimer's disease: From co‐pathology to neurovascular culprit
TDP-43's role in Alzheimer's disease: from accompanying protein to possible blood vessel problem
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Abstract
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 dysfunction.
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Key numbers
50%
TDP-43 Prevalence in AD
TDP-43 pathology is present in over half of Alzheimer's cases.
1/3
Cognitive Decline Association
Approximately one-third of AD cases exhibit TDP-43 pathology.