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Targeting TDP-43 Pathology Alleviates Cognitive and Motor Deficits Caused by Chronic Cerebral Hypoperfusion
Sai Sampath Thammisetty1,2, Laurence Renaud1, Vincent Picher-Martel1,3
1CERVO Brain Research Centre, Quebec City, Canada.
Insights
Chronic brain hypoperfusion causes TDP-43 pathology and cognitive deficits in mice. A novel drug (IMS-088) mitigated these effects, suggesting a potential treatment for vascular dementia.
Area of Science:
- Neuroscience
- Pathology
- Pharmacology
Background:
- Vascular dementia is a common neurodegenerative disease linked to cerebrovascular issues.
- The precise molecular mechanisms and TDP-43 protein's role in vascular dementia are not fully understood.
- TDP-43 mislocalization is a key pathological hallmark observed in neurodegenerative conditions.
Purpose of the Study:
- To investigate the impact of chronic cerebral hypoperfusion (CCH) on TDP-43 pathology and cognitive function in a mouse model.
- To evaluate the therapeutic potential of a novel withaferin A analog (IMS-088) in mitigating CCH-induced neuropathology and deficits.
Main Methods:
- Induction of CCH in mice via unilateral common carotid artery occlusion.
- Assessment of TDP-43 mislocalization, aggregation, microglial activation, and cognitive/motor functions.
- Administration of IMS-088 and evaluation of its effects on TDP-43 pathology, autophagy, and behavioral deficits.
Main Results:
- CCH induced cytoplasmic TDP-43 mislocalization and insoluble phospho-TDP-43 aggregates in mice, mirroring human vascular dementia pathology.
- CCH led to chronic microglial activation, neuroinflammation, cognitive decline, and motor impairments.
- IMS-088 treatment ameliorated TDP-43 pathology, enhanced autophagy, and improved cognitive and motor deficits in CCH mice.
Conclusions:
- TDP-43 pathogenic inclusions are implicated in dementia resulting from chronic brain hypoperfusion.
- Targeting TDP-43 pathology with agents like IMS-088 shows promise for treating vascular dementia.
- The study highlights a potential disease-modifying strategy for hypoperfusion-induced dementia.
Abstract:
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.
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