NLRP3 Inflammasome-Dependent Increases in High Mobility Group Box 1 Involved in the Cognitive Dysfunction Caused by Tau-Overexpression

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.

Reduction of human Alzheimer’s disease risk and reversal of mouse model cognitive deficit with nucleoside analog use

“…Innate immune signaling through the NLRP3 inflammasome has been implicated in the pathogenesis of AD [5][6][7][8][9][10][11][12][13] . A therapy that inhibits inflammasome activation could thus be neuroprotective and improve clinical outcomes in AD.…”

“…; https://doi.org/10.1101/2023.03.17.23287375 doi: medRxiv preprint 4 NLRP3 inflammasome, a multimeric protein complex that responds to aberrant Aβ and tau aggregation by launching a potent inflammatory response characterized by caspase-1 activation, interleukin-1β (IL-1β) release, and neuronal cell death [5][6][7][8] . In turn, NLRP3 activation facilitates further deposition of Aβ plaques and tau fibrils, establishing a positive feedback loop that contributes to the development of AD [9][10][11][12][13] . NLRP3 inflammasome inhibition may protect against AD progression 9,14 .…”

Anti-Inflammatory Activity of 4-(4-(Heptyloxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one via Repression of MAPK/NF-κB Signaling Pathways in β-Amyloid-Induced Alzheimer’s Disease Models

“…Tau pathology has a direct positive correlation with neuroinflammation in the parahippocampus of AD patients examined by positron emission tomography [ 42 ]. Hyperphosphorylated tau trigger neuroinflammation in an NLRP3-dependent manner to activate IL-1β levels and impair spatial memory [ 43 ]. In this study, we found that Aβ 25–35 could promote the release of proinflammatory cytokines, and W112 prevented the over-production of TNF-α and IL-6 both in vitro and in vivo studies.…”

The Role of NLRP3 Inflammasome in Alzheimer’s Disease and Potential Therapeutic Targets

“…Panda et al used tau-derived PHF6 peptide (VQIVYK) to stimulate microglia and found that VQIVYK in the form of fibrous aggregates upregulated the expression of NLRP3 at mRNA and protein levels in a dose- and time-dependent manner, ultimately leading to increased expression of IL-1β and IL-18 ( Panda et al, 2021 ). Experimental results from in vivo also show that hyperphosphorylation of tau in the mouse brain significantly increases the activation of NLRP3 inflammasome and the up-regulation of IL-1β levels ( Zhao et al, 2021 ). In summary, we speculate that the role of tau in NLRP3 inflammasome is similar to Aβ.…”