Targeting TDP-43 Pathology Alleviates Cognitive and Motor Deficits Caused by Chronic Cerebral Hypoperfusion

Neurotherapeutics. 2021 Apr;18(2):1095-1112. doi: 10.1007/s13311-021-01015-8. Epub 2021 Mar 30.


Vascular dementia is one of the most common forms of dementia in aging population. However, the molecular mechanisms involved in development of disease and the link between the cerebrovascular pathology and the cognitive impairments remain elusive. Currently, one common and/or converging neuropathological pathway leading to dementia is the mislocalization and altered functionality of the TDP-43. We recently demonstrated that brain ischemia triggers an age-dependent deregulation of TDP-43 that was associated with exacerbated neurodegeneration. Here, we report that chronic cerebral hypoperfusion in mice (CCH) produced by unilateral common carotid artery occlusion induces cytoplasmic mislocalization of TDP-43 and formation of insoluble phosho-TDP-43 aggregates reminiscent of pathological changes detected in cortical neurons of human brain samples from patients suffering from vascular dementia. Moreover, the CCH in mice caused chronic activation of microglia and innate immune response, development of cognitive deficits, and motor impairments. Oral administration of a novel analog (IMS-088) of withaferin A, an antagonist of nuclear factor-κB essential modulator (NEMO), led to mitigation of TDP-43 pathology, enhancement of autophagy, and amelioration of cognitive/motor deficits in CCH mice. Taken together, our results suggest that targeting TDP-43 pathogenic inclusions may have a disease-modifying effect in dementia caused by chronic brain hypoperfusion.

Keywords: Autophagy; Chronic cerebral hypoperfusion; Dementia; NF-κb; TDP-43.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebrovascular Circulation / drug effects*
  • Cerebrovascular Circulation / physiology
  • Cerebrovascular Disorders / drug therapy
  • Cerebrovascular Disorders / genetics*
  • Cerebrovascular Disorders / pathology
  • Chronic Disease
  • Cognitive Dysfunction / drug therapy
  • Cognitive Dysfunction / genetics*
  • Cognitive Dysfunction / pathology
  • DNA-Binding Proteins / genetics*
  • Drug Delivery Systems / methods
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Disorders / drug therapy
  • Motor Disorders / genetics*
  • Motor Disorders / pathology
  • TDP-43 Proteinopathies / drug therapy
  • TDP-43 Proteinopathies / genetics*
  • TDP-43 Proteinopathies / pathology
  • Withanolides / administration & dosage
  • Withanolides / chemistry


  • DNA-Binding Proteins
  • TDP-43 protein, mouse
  • Withanolides
  • withaferin A