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Characterizing TDP-43 involvement in vascular dementia

Lookup NU author(s): Professor Raj KalariaORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2026 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.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.

Publication metadata

Author(s): Fung M, Chai YL, Cheng Y-L, Tabassum N, Lim VJT, Kalaria RN, Jo D-G, Chen CP, Lai MKP, Arumugam TV

Publication type: Article

Publication status: Published

Journal: Alzheimer's and Dementia

Year: 2026

Volume: 22

Issue: 2

Print publication date: 01/02/2026

Online publication date: 14/02/2026

Acceptance date: 11/01/2026

Date deposited: 23/02/2026

ISSN (print): 1552-5260

ISSN (electronic): 1552-5279

Publisher: John Wiley and Sons Inc

URL: https://doi.org/10.1002/alz.71196

DOI: 10.1002/alz.71196

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