Characterizing TDP‐43 involvement in vascular dementia

TL;DR

The study explores how TDP-43, a protein linked to neurodegeneration, is affected early in vascular dementia models under low blood flow conditions.

Contribution

The paper identifies TDP-43 as a novel, transient target in vascular cognitive impairment under hypoperfusion.

Findings

TDP-43 and phosphorylated TDP-43 show increased expression and mislocalization in vascular dementia models.

Post mortem human vascular dementia brains do not show TDP-43 abnormalities.

TDP-43 pathology is distinct in vascular dementia compared to Alzheimer's and mixed dementia.

Abstract

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.

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.

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