Age-related deregulation of TDP-43 after stroke enhances NF-κB-mediated inflammation and neuronal damage

Abstract

BackgroundTDP-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.MethodsWild-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.ResultsWe 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.ConclusionTogether, 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.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1350-y) contains supplementary material, which is available to authorized users.

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“…There are therefore clinical and experimental data suggesting a bidirectional relationship between cerebral vascular dysfunction and pathological tau. There is evidence from recent studies that TDP-43 pathology, likewise, is associated with cerebral vascular dysfunction, including pericyte loss and small vessel disease [ 114 , 115 ]. Lastly, cerebral ischaemia induces phosphorylation of α-synuclein at serine-129; this is the predominant disease-related modification of α-synuclein in Lewy bodies and neurites in Parkinson disease, and dementia with Lewy bodies, and also is significantly associated with concomitant AD pathology in these Lewy body diseases [ 116 ].…”

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“…Furthermore, an animal study showed that injection of pre-formed α-syn fibrils triggered reactive microgliosis prior to nigral degeneration [81,82]. The level of cytoplasmic TDP-43 increases with age, and it was suggested that TDP-43 is a modulator of inflammation, which activates the nuclear factor kappa-light-chain-enhancer of activated B cells pathways, leading to a deregulation of innate immune response [83].…”

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“…Thus far, our data suggested that low-grade systemic inflammation can promote TDP-43-induced neurodegeneration, resulting in cognitive impairment. Given that the deregulation of TDP-43 can induce neuroinflammation and increase neuronal death through NF-κB signaling [28,44], we decided to explore whether the observed effects were due to alterations in the NF-κB pathway. Our biochemical analysis demonstrated no changes in phosphorylation of NF-κB p65 or IKβα degradation within the confines of our study design (data not shown).…”