Neuroinflammation in Alzheimer disease
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Neuroinflammatory fluid biomarkers in patients with Alzheimer’s disease: a systematic literature review
Neuroinflammation is associated with both early and late stages of the pathophysiology of Alzheimer’s disease (AD). Fluid biomarkers are gaining significance in clinical practice for diagnosis in presymptomatic stages, monitoring, and disease prognosis. This systematic literature review (SLR) aimed to identify fluid biomarkers for neuroinflammation related to clinical stages across the AD continuum and examined long-term outcomes associated with changes in biomarkers.
Costunolide normalizes neuroinflammation and improves neurogenesis deficits in a mouse model of depression through inhibiting microglial Akt/mTOR/NF-κB pathway
Neuroinflammation is crucial for the pathogenesis of major depression. Preclinical studies have shown the potential of anti-inflammatory agents, specifically costunolide (COS), correlate with antidepressant effects. In this study, we investigated the molecular mechanisms underlying the antidepressant actions of COS. Chronic restraint stress (CRS) was induced in male mice. The mice were treated with either intra-DG injection of COS (5 μM, 1 μL per side) or COS (20 mg/kg, i.p.) for 1 week. We showed that administration of COS through the both routes significantly ameliorated the depressive-like behavior in CRS-exposed mice. Furthermore, administration of COS significantly improved chronic stress-induced adult hippocampal neurogenesis deficits in the mice through attenuating microglia-derived neuroinflammation. We demonstrated that COS (5 μM) exerted anti-neuroinflammatory effects in LPS-treated BV2 cells via inhibiting microglial Akt/mTOR/NF-κB pathway; inactivation of mTOR/NF-κB/IL-1β pathway was required for the pro-neurogenic action of COS in CRS-exposed mice. Our results reveal the antidepressant mechanism of COS that is normalizing neuroinflammation to improve neurogenesis deficits, supporting anti-inflammatory agents as a potential therapeutic strategy for depression.
Escherichia Coli K1-colibactin meningitis induces microglial NLRP3/IL-18 exacerbating H3K4me3-synucleinopathy in human inflammatory gut-brain axis
Escherichia coli K1 (E. coli K1) meningitis early occurs in the gastrointestinal and causes severe damage to the central nervous system, including lifelong neurological complications in survivors. However, the cellular mechanism by which E. coli K1 may cause neuropathies is not well understood due to the lack of relevant human multi-organ models for studying multifaceted systemic inflammation across the gut-brain axis. Here, we reconstruct a multicellular model of the human gut-brain axis to identify the neuropathogenic mechanism driven by E. coli K1-colibactin meningitis. We observed that E. coli K1-genotoxic colibactin induced intestinal and peripheral interleukin 6, causing the blood-brain barrier injury and endothelial inflammation via the p38/p65 pathways. Serpin-E1 from the damaged cerebral endothelia induces reactive astrocytes to release IFN-γ, which reduces microglial phagocytosis of E. coli K1 and exacerbates detrimental neuroinflammation via NLRP3/IL-18 axis. Microglial IL-18 elevates neuronal reactive oxidative stress that worsens DNA double-strand breaks in E. coli K1-infected neurons, leading to H3K4 trimethylation and phosphorylation of alpha-synuclein. Our findings suggest therapeutic strategies for post-bacterial meningitis treatment to potentially prevent the initiation of synucleinopathy.
Mettl3-m6A-NPY axis governing neuron–microglia interaction regulates sleep amount of mice
Sleep behavior is regulated by diverse mechanisms including genetics, neuromodulation and environmental signals. However, it remains completely unknown regarding the roles of epitranscriptomics in regulating sleep behavior. In the present study, we showed that the deficiency of RNA m6A methyltransferase Mettl3 in excitatory neurons specifically induces microglia activation, neuroinflammation and neuronal loss in thalamus of mice. Mettl3 deficiency remarkably disrupts sleep rhythm and reduces the amount of non-rapid eye movement sleep. We also showed that Mettl3 regulates neuropeptide Y (NPY) via m6A modification and Mettl3 conditional knockout (cKO) mice displayed significantly decreased expression of NPY in thalamus. In addition, the dynamic distribution pattern of NPY is observed during wake-sleep cycle in cKO mice. Ectopic expression of Mettl3 and NPY significantly inhibits microglia activation and neuronal loss in thalamus, and restores the disrupted sleep behavior of cKO mice. Collectively, our study has revealed the critical function of Mettl3-m6A-NPY axis in regulating sleep behavior.
Exosome-based targeted delivery of NF-κB ameliorates age-related neuroinflammation in the aged mouse brain
Neuroinflammation, a significant contributor to various neurodegenerative diseases, is strongly associated with the aging process; however, to date, no efficacious treatments for neuroinflammation have been developed. In aged mouse brains, the number of infiltrating immune cells increases, and the key transcription factor associated with increased chemokine levels is nuclear factor kappa B (NF-κB). Exosomes are potent therapeutics or drug delivery vehicles for various materials, including proteins and regulatory genes, to target cells. In the present study, we evaluated the therapeutic efficacy of exosomes loaded with a nondegradable form of IκB (Exo-srIκB), which inhibits the nuclear translocation of NF-κB to suppress age-related neuroinflammation. Single-cell RNA sequencing revealed that these anti-inflammatory exosomes targeted macrophages and microglia, reducing the expression of inflammation-related genes. Treatment with Exo-srIκB also suppressed the interactions between macrophages/microglia and T and B cells in the aged brain. We demonstrated that Exo-srIκB successfully alleviates neuroinflammation by primarily targeting activated macrophages and partially modulating the functions of age-related interferon-responsive microglia in the brain. Thus, our findings highlight Exo-srIκB as a potential therapeutic agent for treating age-related neuroinflammation.
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