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Virus-mediated delivery of single-chain antibody targeting TDP-43 protects against neuropathology, cognitive impairment and motor deficit caused by chronic cerebral hypoperfusion

  • 0CERVO Brain Research Centre, Québec, Québec G1J 2G3, Canada.
Experimental Neurology +

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January 8, 2025

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January 8, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

A novel antibody therapy targeting TDP-43 protein aggregates shows promise in preventing cognitive and motor deficits associated with chronic cerebral hypoperfusion, a condition linked to vascular dementia.

Area Of Science

  • Neuroscience
  • Neurodegenerative Diseases
  • Molecular Biology

Background

  • Chronic cerebral hypoperfusion in mice models age-dependent TDP-43 aggregation in cortical neurons.
  • TDP-43 homeostasis deregulation correlates with cognitive and motor deficits, mimicking vascular dementia pathology.
  • TDP-43 protein is implicated in neuronal damage and symptom development in hypoperfusion models.

Purpose Of The Study

  • To investigate the therapeutic potential of targeting TDP-43 aggregation in a mouse model of chronic cerebral hypoperfusion.
  • To evaluate the efficacy of a novel single-chain antibody (scFv-E6) delivered via adeno-associated virus for neuroprotection.

Main Methods

  • Generation of an adeno-associated virus vector encoding scFv-E6 for pan-neuronal transduction.
  • Intravenous administration of the vector prior to inducing permanent unilateral common carotid artery occlusion in mice.
  • Assessment of TDP-43 aggregation, autophagy markers, microgliosis, cognitive function (novel object recognition), and motor performance (grip strength).

Main Results

  • Virus-mediated delivery of scFv-E6 reduced cytoplasmic TDP-43 aggregates in cortical neurons.
  • Treatment boosted autophagy markers and attenuated microgliosis following cerebral hypoperfusion.
  • Neuronal expression of scFv-E6 prevented cognitive impairment and motor deficits induced by hypoperfusion.

Conclusions

  • TDP-43 plays a critical role in neuronal damage and functional deficits caused by chronic cerebral hypoperfusion.
  • The scFv-E6 antibody demonstrates robust protective effects, highlighting TDP-43 as a viable therapeutic target.
  • Antibody-based strategies targeting TDP-43 represent a promising avenue for developing treatments for vascular dementia.

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