In a non-diseased state, a balance between soluble and insoluble forms of RNA binding proteins (including TDP-43) and cell stress granules is maintained in the cytoplasm primarily due to their reversibility during cellular stress response [31]. In ALS and FTLD, this balance is possibly compromised due to the increased presence of aggregated TDP-43 within the cytoplasm, which in turn may increase cellular stress that leads to the formation of additional stress granules and the aggregation of RNA binding proteins, acting as seeds for TDP-43 aggregation [31]. TDP-43 can also be found within stress granules themselves depending on the conditions used to induced stress. For example, stress induced by sodium arsenite produces increased TDP-43 in stress granules [15, 86]. It has also been reported that TDP-43 inclusion bodies co-localize with markers of stress granules [26, 78, 86,87,88,89]. Interestingly, only the full length TDP-43 species, but not the CTFs, are recruited into stress granules, which requires both the RBD1 and GRD domains [90]. On the other hand, some investigators suggested that co-localization of TDP-43 with stress granules depends on RNA-bound forms of TDP-43. RNA-bound TDP-43 in stress granules is soluble, while free TDP-43 can form insoluble aggregates independent of stress granules [15, 91]. Together, the relationship between stress granules and TDP-43 pathology is a research focus that needs further investigation.
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Interestingly, TDP-43 presenting as a secondary comorbid pathology in AD follows its own distinct pathological distribution pattern compared to that of ALS and FTLD. Josephs et al proposed that the progression of TDP-43 pathology in AD occurs in six stages, with stage 1 being characterized by TDP-43 pathology present within the amygdala (Fig 4) [117]. Progression into the entorhinal cortex and subiculum of the hippocampus defines stage 2, while stage 3 involves the hippocampal dentate gyrus and occipitotemporal cortex. In a subset of cases, the hippocampus has neuronal loss and gliosis consistent with hippocampal sclerosis [118, 123], but in other cases TDP-43 pathology is associated with Alzheimer type lesions, in particular neurofibrillary tangles [123]. The phenomenon of TDP-43 colocalization in neurons with neurofibrillary tangles has been termed Type β [131], to distinguish it from genuine NCI in Type B cellular pathology. As the pathology progresses into stage 4, the insular cortex, ventral striatum, basal forebrain, and inferior temporal cortex become affected. In stage 5, TDP-43 pathology now involves the brainstem nuclei, including the substantia nigra, inferior olivary nucleus, and midbrain tectum. The final stage, stage 6, is associated with involvement of basal ganglia and middle frontal cortex [117]. The TDP-43 stage was not affected by the age at onset, nor the time from onset to death in these AD patients [117]. This staging scheme is supported by assessment of clinical behavior, pathological characteristics, neuroimaging, and genetics; however, the underlying mechanisms driving distribution of TDP-43 in AD is unclear.
A study investigating the relationship between TDP-43 and AD found that late stage AD patients have increased pathological cortical TDP-43 [122], which is consistent with the finding that TDP-43 pathology is associated with severe AD pathology [129]. Similar to late-stage AD, the investigators also noted an increase in TDP-43 pathology after Aβ (1-42) expressing lentiviral injections into the cortices of rats, as well as co-localization of intracellular Aβ with TDP-43, and association between phospho-TDP-43 and Aβ [122]. These data suggest a direct relationship between pathological TDP-43 and expression of Aβ in cells [122].
An in vivo study using transgenic mice expressing human TDP-43 mutants found that administration of an autophagy-inducing drug could ameliorate TDP-43 pathology in the brain and spinal cord of the transgenic animals [171]. Given the fact that tau and α-synuclein pathologies also implicate disruption of autophagic pathways [172,173,174], developing active pharmacological agents to enhance autophagy flux may alleviate intracellular aggregation-prone proteins. Due to the ubiquitous nature of TDP-43 expression, it may not be a viable therapeutic approach to target TDP-43 in a generalized manner; however, strategies to modify the TDP-43 toxicity and to reduce TDP-43 aggregation may not only benefit FTLD and ALS patients [175], but also be relevant to more common age-related neurodegenerative disorders such as AD, Lewy body dementia, and LATE.
Other approaches to address the host response directly rather than solely focusing on the virus have included targeting innate immune pathways that amplify inflammatory signals and contribute to epithelial damage. The inflammasome, an innate signaling complex that is required for IL-1β and IL-18 secretion has been implicated in multiple studies as influenza-associated pathology [16, 17]. Suppressing inflammasome activation later in infection, by targeting NLRP3 (a key component of inflammasome signaling) downstream of influenza has had positive effects on recovery in animal models [18, 19]. Following inflammasome activation, secondary cytokine and chemokine signaling can lead to the recruitment of tissue-damaging neutrophil and inflammatory monocyte populations. Experiments blocking CXCR1/2 signaling, a key receptor pathway necessary for neutrophil recruitment to the site of inflammation showed protection in murine infections with influenza, Staphylococcus pneumoniae, or combined infections. Given the prominence of secondary bacterial infections (discussed in detail below) in influenza-associated disease, such host-directed therapies may have significant clinical utility [20]. Neutrophils can mediate tissue damage by secreting high levels of tissue remodeling enzymes such as MMPs, but also amplify inflammation by secreting extracellular traps (NETs). In mouse models, NETs were highly correlated with acute lung injury, which could be exacerbated by shifting cellular infiltrates in favor of neutrophils by depleting macrophages [21]. Similar NET structures have been observed in humans suffering from severe influenza disease. In one study of severe H7N9 and H1N1pdm09 virus infection, levels of NETs at admission were correlated with clinical scores (APACHE II) [22]. 2ff7e9595c
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