Stroke and risk of ALS

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A recent study proposes that age-related dysregulation of TDP-43 exacerbates post-stroke inflammation and ischemic damage and may contribute to neurodegenerative processes. enter image description here Stroke is a leading cause of death and the leading cause of long-term disability. Patients who survive a stroke are at greater risk of later developing vascular and/or Alzheimer-type dementia. This risk is particularly high in the elderly because various cellular processes are altered during aging.

In addition to processes associated with chronic neurodegeneration, a growing body of research suggests that dysregulation of TDP-43 neurons can occur as a result of brain injury, including single and repetitive traumatic brain injury. Researchers have recently shown that aging-associated processes significantly affect microglia activation patterns and innate immune signaling after stroke in aged female and male mice. However, how aging affects immune signaling in neurons and/or microglia/neuron crosstalk in response to ischemic injury remains unclear.

In a new paper, researchers have focused their study on transactive response (TAR) DNA-binding protein 43 (TDP-43). TDP-43 has been identified as a major constituent of ubiquitinated nuclear and cytoplasmic inclusions in fronto temporal degeneration (FTD), ALS, and Alzheimer's disease. While normally localized to the nucleus, in these diseases TDP-43 forms insoluble ubiquitinated inclusions in which it is abnormally phosphorylated and cleaved into C-terminal 35 and 25 kDa fragments lacking the N-terminal nuclear localization signal.

As previous work, notably of famous researchers like Jean-Pierre Julien, suggested that TDP-43 could serve as a modulator of inflammation, by acting as a co-activator of p65 NF-κB, these researchers hypothesized that the age-related progressive accumulation of cytoplasmic TDP-43 could trigger the activation of pathogenic NF-κB pathways, leading to dysregulation of the innate immune response and thus increasing the susceptibility of neurons to ischemic injury.

They therefore designed a study to identify and characterize age-related expression patterns of TDP-43 in neurons and microglia and to assess its role as a modulator of inflammation following ischemic injury.

The observed that accumulation of cytoplasmic TDP-43 was associated with increased microglial activation and innate immune signaling observed 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 12-month-old mice, which showed larger infarcts as well as increased neuronal death.

The researchers then showed that the increase and/or overexpression of cytoplasmic TDP-43 drives the NF-κB response and further increases the levels of pro-inflammatory markers and ischemic damage after stroke. Taken together, their results suggest that TDP-43 may act as a modulator of age-related inflammation after stroke.

The researchers then analyzed post-mortem brains autopsied at different times after a human stroke, hypothesizing that they would find TDP-43 immunoreactive structures located in the cytoplasm of neurons in the periphery and in the central region of the lesion. ischemic. To investigate this issue, they performed immunohistochemical analyzes of post-mortem post-stroke brain tissue autopsied 1 to 5 days after the stroke. The analysis was performed focusing on two distinct regions of the ischemic lesion, the peri-infarction and central region (cortical sections) and compared to the corresponding controls. The analysis was carried out using an anti-human TDP-43 antibody. In healthy areas, the antibody was found present in well circumscribed and positively stained nuclei, while the cytoplasmic compartment was almost completely devoid of TDP-43 immunoreactivity. In contrast, areas with TDP-43 after acute ischemic stroke revealed increased immunoreactivity in the cytoplasm and, in some cases, extending to cell processes.

The increase in cytoplasmic TDP-43 immunoreactivity was greatest at day 5 after stroke. Stroke in humans is therefore associated with increased TDP-43 immunoreactivity in the the cytoplasmic compartment.

One should note that the conclusions are not exactly the same in experiments in mice and post-mortem observation of brains. In the first case, the poorly localized aggregates of TDP-43 are an element favoring the arrival of the stroke, in the other case, it is on the contrary the arrival of the stroke which seems to create the presence of these poorly localized aggregates.

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