Toll-like receptor 4 (TLR4) is a crucial receptor in neuroinflammation and apoptotic neuronal death, and increasing evidences indicated that β2-microglobulin (B2M) is thought to be a major contributor to age-related cognitive decline. In present study, we designed to investigate the effects of TLR4 on B2M-induced age-related cognitive decline. Wild-type (WT) C57BL/6, TLR4 knockout (TLR4 -KO) mice and hippocampal neurons from the two type mice were respectively divided into two groups: (1) Veh group; (2) B2M-treated group. The behavioral responses of mice were measured using Morris Water Maze. Hippocampal neurogenesis and neuronal damage, inflammatory response, apoptosis, synaptic proteins and neurotrophic factors, and TLR4/MyD88/NF-κB signaling pathway proteins were examined using molecular biological or histopathological methods. The results showed that WT mice received B2M in the DG exhibited age-related cognitive declines, increased TLR4 mRNA expression and high levels of interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α) and apoptotic neuronal death in the hippocampus, which were partially attenuated in TLR4-KO mice. Moreover, in absence of TLR4, B2M treatment improved hippocampus neurogenesis and increased synaptic related proteins. Our cell experiments further demonstrated that deletion of TLR4 could significantly increase synaptic related protein, decrease neuroinflammatory fators, inhibited apoptotic neuronal death, and regulated MyD88/NF-κB signal pathway after B2M treatment. In summary, our results support the TLR4 contributes to B2M-induced age-related cognitive decline due to neuroinflammation and apoptosis through TLR4/MyD88/NF-κB signaling pathway via a modulation of hippocampal neurogenesis and synaptic function. This may provide an important neuroprotective mechanism for improving age-related cognitive decline.

Background: Dexmedetomidine is recommended for sedation in patients on mechanical ventilation. Whether age or ICU types could alter mortality in invasive mechanically ventilated patients with sepsis receiving dexmedetomidine is unknown.Methods: We included patients with sepsis receiving invasive mechanical ventilation from the Medical Information Mart for Intensive Care IV database. The exposure was intravenous dexmedetomidine administration during ICU stay. The primary outcome was 28-day mortality. The secondary outcomes were the length of ICU stay and liberation from invasive mechanical ventilation. Propensity score matching (PSM) and Cox proportional hazards regression were used to adjust for confounders and investigate any association. Restricted cubic spline models were used to evaluate potential nonlinear associations.Results: The pre-matched and propensity score-matched cohorts included 5,871 and 2016 patients, respectively. In the PSM cohorts, dexmedetomidine exposure was related to lower 28-day mortality (186 [17.7%] vs. 319 [30.3%]; p < 0.001). Patients receiving dexmedetomidine, regardless of whether they were younger (≤65 years; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.23–0.42; p < 0.001) or elderly (>65 years; HR, 0.65; 95% CI, 0.52–0.83; p < 0.001), was associated with lower 28-day mortality (61 [10.3%] vs. 168 [28.2%] for younger; 125 [27.2%] vs. 152 [33.0%] for elderly). Patients receiving dexmedetomidine was also associated with lower 28-day mortality (53 [12.6%] vs. 113 [26.5%] for surgical intensive care unit [SICU]; 133 [21.0%] vs. 206 [32.9%] for non-SICU) regardless of whether the first admission to the SICU (HR, 0.36; 95% CI, 0.25–0.50; p < 0.001) or non-SICU (HR, 0.50; 95% CI, 0.40–0.62; p < 0.001). Moreover, both dose and duration of dexmedetomidine administration were related to lower 28-day mortality than no dexmedetomidine in younger patients (p < 0.001), but it not statistically significant in elderly patients.Conclusion: Dexmedetomidine was associated with lower 28-day mortality in critically ill patients with sepsis receiving invasive mechanical ventilation, regardless of whether patients were younger or elderly, the first admission to the SICU or non-SICU.

Neuropathic pain (NP) is associated with sleep disturbances, which may substantially influence the quality of life. Clinical and animal studies demonstrated that neurotransmitter is one of the main contributors to cause sleep disturbances induced by NP. Recently, it was reported that P2X7 receptors (P2X7R) are widely expressed in microglia, which serves crucial role in neuronal activity in the pain and sleep-awake cycle. In this study, we adopted the chronic constriction injury (CCI) model to establish the progress of chronic pain and investigated whether P2X7R of microglia in cortex played a critical role in sleep disturbance induced by NP. At electroencephalogram (EEG) level, sleep disturbance was observed in mice treated with CCI as they exhibited mechanical and thermal hypersensitivity, and inhibition of P2X7R ameliorated these changes. We showed a dramatic high level of P2X7R and Iba-1 co-expression in the cortical region, and the inhibition of P2X7R also adversely affected it. Furthermore, the power of LFPs in ventral posterior nucleus (VP) and primary somatosensory cortex (S1) which changed in the CCI group was adverse after the inhibition of P2X7R. Furthermore, inhibition of P2X7R also decreased the VP-S1 coherence which increased in CCI group. Nuclear magnetic resonance demonstrated inhibition of P2X7R decreased glutamate (Glu) levels in thalamic and cortical regions which were significantly increased in the CCI mice. Our findings provide evidence that NP has a critical effect on neuronal activity linked to sleep and may built up a new target for the development of sleep disturbances under chronic pain conditions.

Postoperative delirium (POD) is a serious and prevalent neurocognitive complication that poses a major clinical challenge because its mechanism is unclear. This study identifies a pathogenic pathway centred on the direct interaction between transient receptor potential vanilloid 4 (TRPV4) and the essential N-methyl-D-aspartate receptor (NMDAR) subunit GluN1. Using a murine POD model, the neuron-centric glutamatergic dysfunction in the hippocampus was initially confirmed through ex vivo metabolic kinetic analysis. Transcriptomic analysis revealed upregulation of Trpv4 , predominantly in neurons. Co-immunoprecipitation coupled with mass spectrometry revealed that TRPV4 directly interacts with GluN1. This enhanced TRPV4-GluN1 coupling promoted GluN1 phosphorylation at serine 896 and hyperactivated NMDAR signalling. We subsequently observed the concurrent induction of endoplasmic reticulum (ER) stress, as evidenced by a dilated ER ultrastructure and the upregulation of the expression of UPR markers (ATF6, p-PERK, p-IRE1α, and CHOP), as well as neuroinflammation, characterized by microglial activation and elevated expression of proinflammatory mediators (IL-6, IL-1β, and ICAM-1). These molecular pathologies were associated with decreased neuronal activity and the characteristic cognitive-affective deficits associated with POD. Critically, both pharmacological inhibition of TRPV4 (HC067047) and hippocampal CA3-specific Trpv4 knockdown reversed these pathologies and rescued the behaviour. Inhibiting NMDAR with MK801 recapitulated these therapeutic benefits. Furthermore, TRPV4 was significantly upregulated in early-onset Alzheimer’s disease patients. Our study defines a novel TRPV4-GluN1 axis that drives POD pathogenesis, suggesting that it is a promising therapeutic target.