Targeting TDP-43 Pathology Alleviates Cognitive And Motor Deficits In Mice Caused By Chronic Cerebral Hypoperfusion

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Vascular cognitive disorders represent an interesting intersection between cardiovascular disease and neurodegenerative disorders such as Alzheimer's disease. enter image description here A slice of brain of a person who had a stroke By Marvin 101 - via Wikipedia

Scientists have previously reported the formation of ubiquitinated TDP-43 cytoplasmic inclusions after stroke. As TDP-43 inclusions have been mainly associated with several chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and more particularly amyotrophic lateral sclerosis, it is important to know if these diseases can occur as a result of cerebral lesions.

Scientists in Jean-Pierre Julien's group are studying age-related expression patterns of TDP-43 in neurons and glia and its role as a modulator of inflammation after ischemic injury.

In this new publication, the authors report that chronic cerebral hypoperfusion in mice (chronic cerebral hypoperfusion) produced by unilateral occlusion of the common carotid artery, induces poor cytoplasmic localization of TDP-43 and the formation of aggregates. insoluble phosho-TDP-43 reminiscent of pathological changes detected in the cortical. neurons from human brain samples from patients with vascular dementia.

Their results suggest that the level of cytoplasmic TDP-43 increases with aging and may act as an age-related mediator of inflammation and neuronal damage after stroke. Thus, targeting cytoplasmic TDP-43, for example with IMS-088 which is developed by Imstar, may have therapeutic potential after a stroke.

In a previous experiment conducted by the authors, wild-type and TDP-43 transgenic mice of different age groups were subjected to transient occlusion of the middle cerebral artery. The role of TDP-43 in the modulation of inflammation was then evaluated using immunofluorescence, Western blot analysis and in vivo bioluminescence imaging. Finally, post-mortem human brain sections were analyzed to detect the TDP-43 protein by immunohistochemistry.

The deregulation observed in TDP-43 expression profiles was associated with increased microglial activation and innate immune signaling. The presence of ubiquitinated TDP-43 aggregates and its cleaved TDP-35 and TDP-25 fragments was markedly increased in 12 month old mice, resulting in larger infarcts and a significant increase in neuronal death.

It is important to note that, unlike the characteristic neuropathological features associated with chronic neurodegenerative disorders, the TDP-43 positive cytoplasmic inclusions detected after stroke were not phosphorylated.

Next, the authors had shown that an increase and / or overexpression of cytoplasmic TDP-43 elicits the pathogenic NF-κB response and further increases the levels of pro-inflammatory markers and ischemic damage after stroke in a age. The NF-κB pathway is one of the main pathways that regulate neuroinflammation and can be activated by various inflammatory attacks, in particular bacterial lipopolysaccharide or TNF-α. Finally, post-mortem stroke brain tissue analyzes revealed the presence of TDP-43 cytoplasmic immunoreactive structures after human stroke.

In addition, chronic cerebral hypoperfusion in mice had caused chronic activation of microglia and the innate immune response, the development of cognitive deficits and motor disturbances.

Oral administration of a novel analogue (IMS-088) of withaferin A, an antagonist of the essential nuclear factor-κB modulator (NEMO), led to the alleviation of the TDP-43 pathology, the improvement of autophagy and improvement of cognitive / motor deficits in chronic diseases. cerebral hypoperfusion mouse.

Side and unwanted effects are suspected for Whitania extracts. Withaferin-A is a withanolide, mainly present in Ashwagandha (Withania somnifera). Withaferin-A has been shown to have anticancer activity through various mechanisms including activation of caspase-3 and pERK, inhibition of pro-survival JNK, Akt and IL6 signaling, l 'oxidative stress inducement and DNA damage response (DDR).

Withaferin-A is sometimes obtained by bioconversion of Withania somnifera extract by subjecting it to fermentation with the fungus Beauveria bassiana.


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