Baicalin inhibits LPS/IFN-γ-induced inflammation via TREM2/TLR4/NF-κB pathway in BV2 cells / 中国中药杂志

This study investigated the mechanism of baicalin on lipopolysaccharide(LPS)/interferon γ(IFN-γ)-induced inflammatory microglia based on the triggering receptor expressed on myeloid cells 2(TREM2)/Toll-like receptor 4(TLR4)/nuclear factor kappaB(NF-κB) pathway. Specifically, LPS and IFN-γ were used to induce inflammation in mouse microglia BV2 cells. Then the normal group, model group, low-dose(5 μmol·L~(-1)) baicalin group, medium-dose(10 μmol·L~(-1)) baicalin group, high-dose(20 μmol·L~(-1)) baicalin group, and minocycline(10 μmol·L~(-1)) group were designed. Cell viability was detected by CCK-8 assay and cell morphology was observed under bright field. The expression of interleukin-1β(IL-1β), interleukin-4(IL-4), inducible nitric oxide synthase(iNOS), interleukin-6(IL-6), interleukin-10(IL-10), and arginase-1(Arg-1) mRNA was detected by real-time quantitative PCR, the protein expression of tumor necrosis factor-α(TNF-α), IL-1β, TREM2, TLR4, inhibitor kappaB-alpha(IκBα), p-IκBα, NF-κB p65 and p-NF-κB p65 by Western blot, and transfer of NF-κB p65 from cytoplasm to nucleus by cellular immunofluorescence. Compared with the normal group, most of the BV2 cells in the model group tended to demonstrate the pro-inflammatory M1 amoeba morphology, and the model group showed significant increase in the mRNA levels of IL-1β, IL-6, and iNOS, decrease in the mRNA levels of IL-4, IL-10, and Arg-1(P<0.01), rise of the protein expression of TNF-α, IL-1β, TLR4, p-IκBα, and p-NF-κB p65(P<0.01), reduction in TREM2 protein expression, and increase in the expression of NF-κB p65 in nucleus. Compared with the model group, baicalin groups and minocycline group showed the recovery of BV2 cell morphology, significant decrease in the mRNA levels of IL-1β, IL-6 and iNOS, increase in the mRNA levels of IL-4, IL-10, and Arg-1(P<0.01), reduction in the protein expression of TNF-α, IL-1β, TLR4, p-IκBα, and p-NF-κB p65(P<0.05), rise of TREM2 protein expression, and decrease in the expression of NF-κB p65 in nucleus. In summary, these results suggest that baicalin can regulate the imbalance between TREM2 and TLR4 of microglia and inhibit the activation of downstream NF-κB, thus promoting the polarization of microglia from pro-inflammatory phenotype to anti-inflammatory phenotype.

Up-Regulation of Trem2 Inhibits Hippocampal Neuronal Apoptosis and Alleviates Oxidative Stress in Epilepsy via the PI3K/Akt Pathway in Mice / 神经科学通报·英文版

Epilepsy is a chronic and severe neurological disorder that has negative effects on the autonomous activities of patients. Functionally, Trem2 (triggering receptor expressed on myeloid cells-2) is an immunoglobulin receptor that affects neurological and psychiatric genetic diseases. Based on this rationale, we aimed to assess the potential role of Trem2 integration with the PI3K/Akt pathway in epilepsy. We used microarray-based gene expression profiling to identify epilepsy-related differentially-expressed genes. In a mouse hippocampal neuron model of epilepsy, neurons were treated with low-Mg extracellular fluid, and the protein and mRNA expression of Trem2 were determined. Using a gain-of-function approach with Trem2, neuronal apoptosis and its related factors were assessed by flow cytometry, RT-qPCR, and Western blot analysis. In a pilocarpine-induced epileptic mouse model, the malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) content and superoxide dismutase (SOD) and glutathione-peroxidase (GSH-Px) activity in the hippocampus were determined, and the protein expression of Trem2 was measured. In addition, the regulatory effect of Trem2 on the PI3K/Akt pathway was analyzed by inhibiting this pathway in both the cell and mouse models of epilepsy. Trem2 was found to occupy a core position and was correlated with epilepsy. Trem2 was decreased in the hippocampus of epileptic mice and epileptic hippocampal neurons. Of crucial importance, overexpression of Trem2 activated the PI3K/Akt pathway to inhibit neuronal apoptosis. Moreover, activation of the PI3K/Akt pathway through over-expression of Trem2 alleviated oxidative stress, as shown by the increased expression of SOD and GSH-Px and the decreased expression of MDA and 8-OHdG. The current study defines the potential role of Trem2 in inhibiting the development of epilepsy, indicating that Trem2 up-regulation alleviates hippocampal neuronal injury and oxidative stress, and inhibits neuronal apoptosis in epilepsy by activating the PI3K/Akt pathway.

Research progress of TREM2 in Alzheimer disease / 中国药理学与毒理学杂志

Alzheimer disease (AD) is a common neurodegenerative disease in the elderly, but nowadays the pathogenesis of AD is unclear. Myeloid cell 2 trigger receptor (TREM2) is one of the most famous and most common rare mutations in neurodegenerative disease research, and its functional site mutation can significantly increase the incidence of AD. In this paper, we summary the structure, localization, and function and related signaling pathways of TREM2, review the latest epide?miological findings of TREM2 associated with the pathogenesis of AD, and speculate on the possible role of TREM2 in the progression of this disease, as well as the expression of TREM2 and the role of soluble TREM2 in AD brain are further elucidated. Based on the potential protective effect of TREM2 in the pathogenesis of AD, Therefore, targeting TREM2 may provide new opportunities and a reference for AD treatment. As the TREM2 variant appears to be widely involved in neurodegenerative diseases, there is an urgent need to further study the function of TREM2 in the brain and to find its ligands involved in TREM2-mediated signaling transduction and its specific role in AD pathogenesis.

A Case of Nasu-Hakola Disease without Fractures or Consanguinity Diagnosed Using Exome Sequencing and Treated with Sodium Valproate

Nasu-Hakola disease (NHD) is a rare autosomal recessive neuropsychiatric disorder characterized by bone cysts, fractures, and cognitive impairment. Two genes are responsible for the development of NHD; TYROBP and TREM2. Although it presents with typical signs and symptoms, diagnosing this disease remains difficult. This case report describes a male with NHD with no family or past history of bone fractures who was diagnosed using exome sequencing. His frontal lobe psychiatric symptoms recovered partially following treatment with sodium valproate, but not with an antipsychotic.

Nuevos genes descubiertos relacionados con la Enfermedad de Alzheimer / New genes discovered related to Alzheimer's Disease

La Enfermedad de Alzheimer es un problema neurodegenerativo cuyas causas aún no están bien definidas, sin embargo, existen distintas relaciones entre cambios genéticos y la presencia de los síntomas y signos de la enfermedad. Entre ellos están los genes ya conocidos APP, PSEN1 y PSEN2. Con los nuevos avances científicos, se conocen nuevos genes relacionados a esta enfermedad como lo son el gen CHAT, APOE, 5-HTTLPR, SORLI, NINJ2, CST3, EXOC3L2, CLU, NGFR, TREM2, APOC1, ACE, SLC2A14, entre otros. La relación entre estos genes y la enfermedad es muy estrecha y podría ser la brecha en encontrar una posible cura.

Alzheimer's disease is a neurodegenerative problem which cause is not well defined, however, there are different relationships between genetic changes and the presence of symptoms and signs of the disease. Among them, there are some well known such as the APP gene, PSEN 1 and PSEN2. With new scientific advances now we know new genes associated with the disease such as the CHAT, APOE, 5-HTTLPR, SORLI, NINJ2, CST3, EXOC3L2, CLU, NGFR, TREM2, APOCI, ACE, SLC2A14 genes, among others. The knowledge about these genes and the disease could help to find the cure.