withaferin-a and TDP-43-Proteinopathies

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.

Topics: Animals; Cerebrovascular Circulation; Cerebrovascular Disorders; Chronic Disease; Cognitive Dysfunction; DNA-Binding Proteins; Drug Delivery Systems; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Disorders; TDP-43 Proteinopathies; Withanolides

Abnormal cytoplasmic mislocalization of transactive response DNA binding protein 43 (TARDBP or TDP-43) in degenerating neurons is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Our previous work suggested that nuclear factor kappa B (NF-κB) may constitute a therapeutic target for TDP-43-mediated disease. Here, we investigated the effects of root extract of Withania somnifera (Ashwagandha), an herbal medicine with anti-inflammatory properties, in transgenic mice expressing a genomic fragment encoding human TDP-43

Topics: Amyotrophic Lateral Sclerosis; Animals; Avoidance Learning; Cells, Cultured; Cytokines; Disease Models, Animal; DNA-Binding Proteins; Encephalitis; Female; Frontotemporal Lobar Degeneration; Male; Mice; Mice, Transgenic; Microglia; Motor Activity; Neuromuscular Junction; Neurons; NF-kappa B; Plant Extracts; Rotarod Performance Test; Spinal Cord; TDP-43 Proteinopathies; Withania