Characterizing TDP-43 involvement in vascular dementia.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Authors
Fung Fung, Chai Chai, Cheng Cheng, Tabassum Tabassum, Lim Lim, Kalaria Kalaria, Jo Jo, Chen Chen, Lai Lai, Arumugam Arumugam
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