Characterizing TDP‐43 involvement in vascular dementia

Abstract INTRODUCTION Vascular dementia (VaD) is a major therapeutic challenge. Tar DNA‐binding protein 43 (TDP‐43), known for its role in neurodegeneration, may contribute to VaD pathogenesis under chronic cerebral hypoperfusion (CCH). This study investigates TDP‐43 dysregulation in VaD. METHODS TDP‐43 and phosphorylated TDP‐43 (pTDP‐43) expression and localization were assessed in a VaD animal model, neuronal cells exposed to oxygen–glucose deprivation (OGD), and post mortem human brain tissues. RESULTS Bilateral Common Carotid Artery Stenosis (BCAS)‐induced CCH led to increased pTDP‐43 and aberrant redistribution of both TDP‐43 and pTDP‐43. In vitro OGD triggered similar mislocalization. Post mortem VaD brains showed no TDP‐43 abnormalities, while Alzheimer's and mixed dementia cases exhibited marked pathology. DISCUSSION TDP‐43 dysregulation appears early in VaD under hypoperfusive stress, distinguishing it from other dementia subtypes. These findings indicate that TDP‑43 may warrant further investigation as a potential early molecular feature of VaD. Highlights Tar DNA‐binding protein 43 (TDP‐43) is dysregulated early in vascular dementia models. Hypoperfusion triggers TDP‐43 mislocalization and phosphorylation. TDP‐43 pathology is absent in late‐stage human vascular dementia. TDP‐43 is a transient, novel target for vascular cognitive impairment.