Abstract
Tau hyperphosphorylation is a characteristic alteration present in a range of neurological conditions, such as traumatic brain injury (TBI) and neurodegenerative diseases. Treatments targeting high-mobility group box protein 1 (HMGB1) induce neuroprotective effects in these neuropathologic conditions. However, little is known about the interactions between hyperphosphorylated tau and HMGB1 in neuroinflammation. We established a model of TBI with controlled cortical impacts (CCIs) and a tau hyperphosphorylation model by injecting the virus encoding human P301S tau in mice, and immunofluorescence, western blotting analysis, and behavioral tests were performed to clarify the interaction between phosphorylated tau (p-tau) and HMGB1 levels. We demonstrated that p-tau and HMGB1 were elevated in the spatial memory-related brain regions in mice with TBI and tau-overexpression. Animals with tau-overexpression also had significantly increased nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation, which manifested as increases in apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), activating caspase-1 and interleukin 1 beta (IL-1β) levels. In addition, NLRP3–/– mice and the HMGB1 inhibitor, glycyrrhizin, were used to explore therapeutic strategies for diseases with p-tau overexpression. Compared with wild-type (WT) mice with tau-overexpression, downregulation of p-tau and HMGB1 was observed in NLRP3–/– mice, indicating that HMGB1 alterations were NLRP3-dependent. Moreover, treatment with glycyrrhizin at a late stage markedly reduced p-tau levels and improved performance in the Y- and T-mazes and the ability of tau-overexpressing mice to build nests, which revealed improvements in spatial memory and advanced hippocampal function. The findings identified that p-tau has a triggering role in the modulation of neuroinflammation and spatial memory in an NLRP3-dependent manner, and suggest that treatment with HMGB1 inhibitors may be a better therapeutic strategy for tauopathies.
Highlights
The accumulation of phosphorylated tau is a characteristic change in tauopathy and other neurodegenerative diseases
The ipsilateral hippocampus was lacking, a significant increase in high-mobility group box protein 1 (HMGB1) immunoactivity was observed at 4 weeks post injury in the contralateral dentate gyrus (DG) and ipsilateral thalamus compared with the sham group, and this change existed for 8 weeks after the brain injury (Figures 1B–D)
As the previous study found that p-tau (Ser404) increased obviously after traumatic brain injury (TBI) in mice, we investigated p-tau and found that it increased significantly in the above two brain regions at 4 and 8 weeks post injury (Figures 1B–D)
Summary
The accumulation of phosphorylated tau is a characteristic change in tauopathy and other neurodegenerative diseases. Recent evidence has shown that behavioral disorders are more closely associated with a high level of p-tau after TBI than with amyloid-beta (Aβ; Chen et al, 2009; Huber et al, 2013; Tweedie et al, 2013; Takahata et al, 2017). These abnormalities related to tau occur as early as several months to years after trauma; hyperphosphorylated tau is considered the “trigger” of AD (Bramlett and Dietrich, 2015; Johnson et al, 2017). The distribution and spread of p-tau in brain regions varies depending on the type of neurodegenerative disease (Kaufman et al, 2016), and the mechanisms by which abnormal tau leads to neuropathological alterations and cognitive damage have not been fully clarified
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