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TitleAge-related deregulation of TDP-43 after stroke enhances NF-κB-mediated inflammation and neuronal damage.
Publication TypeJournal Article
Year of Publication2018
AuthorsThammisetty, Sai Sampath, Jordi Pedragosa, Yuan Cheng Weng, Frédéric Calon, Anna Planas, and Jasna Kriz
JournalJ Neuroinflammation
Volume15
Issue1
Pagination312
Date Published2018 Nov 09
ISSN1742-2094
Abstract

BACKGROUND: TDP-43 has been identified as a disease-associated protein in several chronic neurodegenerative disorders and increasing evidence suggests its potentially pathogenic role following brain injuries. Normally expressed in nucleus, under pathological conditions TDP-43 forms cytoplasmic ubiquitinated inclusions in which it is abnormally phosphorylated and cleaved to generate a 35 and a 25 kDa C-terminal fragments. In the present study, we investigated age-related expression patterns of TDP-43 in neurons and glia and its role as modulator of inflammation following ischemic injury.

METHODS: Wild-type and TDP-43 transgenic mice of different age groups were subjected to transient middle cerebral artery occlusion. The role of TDP-43 in modulation of inflammation was assessed using immunofluorescence, Western blot analysis, and in vivo bioluminescence imaging. Finally, post-mortem stroke human brain sections were analyzed for TDP-43 protein by immunohistochemistry.

RESULTS: We report here an age-related increase and formation of ubiquitinated TDP-43 cytoplasmic inclusions after stroke. The observed deregulation in TDP-43 expression patterns was associated with an increase in microglial activation and innate immune signaling as revealed by in vivo bioluminescence imaging and immunofluorescence analysis. The presence of ubiquitinated TDP-43 aggregates and its cleaved TDP-35 and TDP-25 fragments was markedly increased in older, 12-month-old mice leading to larger infarctions and a significant increase in in neuronal death. Importantly, unlike the hallmark neuropathological features associated with chronic neurodegenerative disorders, the TDP-43-positive cytoplasmic inclusions detected after stroke were not phosphorylated. Next, we showed that an increase and/or overexpression of the cytoplasmic TDP-43 drives the pathogenic NF-κB response and further increases levels of pro-inflammatory markers and ischemic injury after stroke in age-dependent manner. Finally, analyses of the post-mortem stroke brain tissues revealed the presence of the cytoplasmic TDP-43 immunoreactive structures after human stroke.

CONCLUSION: Together, our findings suggest that the level of cytoplasmic TDP-43 increases with aging and may act as an age-related mediator of inflammation and neuronal injury after stroke. Thus, targeting cytoplasmic TDP-43 may have a therapeutic potential after stroke.

DOI10.1186/s12974-018-1350-y
Alternate JournalJ Neuroinflammation
PubMed ID30413172
PubMed Central IDPMC6230239
Grant ListG-17-0018372 / / Heart and Stroke Foundation of Canada /
93769 / / Canadian Institutes of Health Research / Canada
Team 2 / / Canadian Consortium on neurodgeneration in aging /