The Alzheimer's disease-associated gene TREML2 modulates inflammation by regulating microglia polarization and NLRP3 inflammasome activation

Triggering receptor expressed on myeloid cells-like 2(TREML2)is a newly identified susceptibility gene for Alzheimer's disease(AD).It encodes a microglial inflammation-associated receptor.To date,the potential role of mic roglial TREML2 in neuroinflammation in the context of AD remains unclear.In this study,APP/PS1 mice were used to investigate the dynamic changes of TREML2 levels in brain during AD progression.In addition,lipopolysaccharide(LPS)stimulation of primary microglia as well as a lentivirus-mediated TREML2 overexpression and knockdown were employed to explore the role of TREML2 in neuroinflammation in the context of AD.Our res ults show that TREML2 levels gradually increased in the brains of AP P/PS1 mice during disease progression.LPS stimulation of primary microglia led to the release of inflammato ry cytokines including interleukin-1β,inte rleukin-6,and tumor necrosis factor-a in the culture medium.The LPS-induced mic roglial release of inflammatory cytokines was enhanced by TREML2 overexpression and was attenuated by TREML2 knoc kdown.LPS increased the levels of mic roglial M1-type polarization marker inducible nitric oxide synthase.This effect was enhanced by TREML2 overexpression and ameliorated by TREML2 knockdown.Furthermore,the levels of microglial M2-type polarization markers CD206 and ARG1 in the primary microglia were reduced by TREML2 overexpression and elevated by TREML2 knockdown.LPS stimulation increased the levels of NLRP3 in primary microglia.The LPS-induced increase in NLRP3 was further elevated by TREML2 overexpression and alleviated by TREML2 knockdown.In summary,this study provides the first evidence that TREML2 modulates inflammation by regulating microglial polarization and NLRP3 inflammasome activation.These findings reveal the mechanisms by which TREML2 regulates microglial inflammation and suggest that TREML2 inhibition may represent a novel therapeutic strategy for AD.

Lamotrigine protects against cognitive deficits,synapse and nerve cell damage,and hallmark neuropathologies in a mouse model of Alzheimer’s disease

Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular mechanisms remain unclear.In this study,amyloid precursor protein/presenilin 1(APP/PS1)double transgenic mice were used as a model of Alzheimer’s disease.Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months.The cognitive functions of animals were assessed using Morris water maze.Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay.The cell damage in the brain was investigated using hematoxylin and eosin staining.The levels of amyloid-βand the concentrations of interleukin-1β,interleukin-6 and tumor necrosis factor-αin the brain were measured using enzyme-linked immunosorbent assay.Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction.We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice;alleviated damage to synapses and nerve cells in the brain;and reduced amyloid-βlevels,tau protein hyperphosphorylation,and inflammatory responses.High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds,Cd74,Map3k1,Fosb,and Spp1 expression in the brain.These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease.Furthermore,these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease.

The Flow Behavior of Red Blood Cell Reduced Deformability in Microchannel

Blood cells are mainly(~99%)comprised of red blood cells.The most remarkable properties of are their high deformability,which allow they flow through microcapillaries of diameter even smaller than their size.The RBC’s remarkable mechanical properties originate from the unique architecture of its membrane.To study the mechanism of RBC’s deformability,a commonly adopted approach is to localize the cytoskeleton protein by immunofluorescence,followed by exploring the changes of cytoskeleton protein during cell deformation.During this process,the fixed treatment of RBC using GA and PFA is of great importance.However,RBC’s deformability is reduced by the fixation process and skeletal protein of membrane is changed accordingly.The flow behavior of red RBCs through the microchannel also changed.Given the difficulty of observing RBC flow in vivo,in vitro simulation by virtue of microfluidic devices provides a feasible alternative.An important physiological phenomenon of the blood flow is the formation of cell free layer(CFL),with RBCs show a tendency to concentrate towards the central axis of the pipeline and move faster than the plasma layer.However,this phenomena is weaken if the stiffness of the membrane increase,which occurs in some disease,such as hereditary spherocytosis and hereditary elliptocytosis.To study the effects of GA and PFA fix treatment on RBC deformability,a microfluidic platform is employed to measuring the CFL and flow velocity of blood flow in this work.The PDMS micro flow channel used is 100 micrometers in width and 50 micrometers in deep.The RBC suspension is fed into the flow channel by the injection pump(NE-1000.USA),and the experiments are observed and recorded by the inverted microscope(IX70,Olympus,Japan)and high-speed camera(Memrecam GX-1,NAC,Japan)system.Three GA concentrations,i.e.,0.000 5,0.000 75,and 0.001 wt.%were used.Meanwhile,the effect of PFA at a concentration of 2wt.%work with GA was also investigated.Images of the flowing RBCs are processed mainly based on Memrecam GXLink.The results show that,the diameter of the RBC be treated is bigger and the shape of the RBC is became more flat after treated.Some of RBCs lost their biconcave structure.When the RBC suspension with 5%Hct flow in the microchannel,the CFL thickness decrease after being treated.And with concentrations of GA increase,the CFL thickness become thinner.The CFL thickness decrease significantly when GA and 2 wt.%PFA work combined.The velocity of RBCs decreases after treated with the GA or/and 2wt.%PFA.GA is known to relieve the dissolution of red blood cells during fluorescence labeling.On the other hand,the crosslinking of the aldehyde group(-cho)of GA with the amino group(-nh2)of RBC membrane protein will change the conformation of the membrane protein and its visco-elastic properties in turn.Then,the transparent fluidity orrheology characteristics of RBC is altered.Since GA and PFA are commonly used to immobilize red blood cells and keep the fluorescence constant,and PFA works similarly as GA,as a result,the variation of membrane protein conformation is intensified,and the membrane becomes stiffer.

Dose-response relationship between risk factors and incidence of COVID-19 in 325 hospitalized patients:A multicenter retrospective cohort study

BACKGROUND The epidemiological and clinical characteristics of coronavirus disease 2019(COVID-19)patients have been widely reported,but the assessment of doseresponse relationships and risk factors for mortality and severe cases and clinical outcomes remain unclear.AIM To determine the dose-response relationship between risk factors and incidence of COVID-19.METHODS In this retrospective,multicenter cohort study,we included patients with confirmed COVID-19 infection who had been discharged or had died by February 6,2020.We used multivariable logistic regression and Cox proportional hazard models to determine the dose-response relationship between risk factors and incidence of COVID-19.RESULTS It clarified that increasing risk of in-hospital death were associated with older age(HR:1.04,95%CI:1.01-1.09),higher lactate dehydrogenase[HR:1.04,95%confidence interval(CI):1.01-1.10],C-reactive protein(HR:1.10,95%CI:1.01-1.23),and procalcitonin(natural log-transformed HR:1.88,95%CI:1.22-2.88),and D-dimer greater than 1μg/m L at admission(natural log transformed HR:1.63,95%CI:1.03-2.58)by multivariable regression.D-dimer and procalcitonin were logarithmically correlated with COVID-19 mortality risk,while there was a linear dose-response correlation between age,lactate dehydrogenase,D-dimer and procalcitonin,independent of established risk factors.CONCLUSION Higher lactate dehydrogenase,D-dimer,and procalcitonin levels were independently associated with a dose-response increased risk of COVID-19 mortality.

Photobiomodulation:A Potential Non-invasive Method to Alleviate Neurological Events Following COVID-19 Infection

In the past several months,confirmed cases have surged as many countries have loosened their bans on Coronavirus disease 2019(COVID-19)epidemic prevention and control.As a respiratory infectious disease caused by a novel coronavirus called SARS-CoV-2,COVID-19 emerged in late December 2019 and lasted for more than three years worldwide[1].

Inhibition of ALDH2 by disulfiram leads to synthetic lethality via ROS strikes twice in ARID1A-deficient cholangiocarcinoma

Synthetic lethality describes an interaction whereby the co-occurrence of two mutations leads to cell death but one mutation alone does not,which can be exploited for cancer therapeutics.1 Due to lacking effective nonsurgical treatment and early clinical diagnosis markers,patients have high mortality and low overall survival rates in cholangiocarcinoma(CCA).

Cytoprotective Mechanism of the Novel Gastric Peptide BPC157 in Gastrointestinal Tract and Cultured Enteric Neurons and Glial Cells

Dear Editor,Body protection compound (BPC) 157 is a stable gastric pentadecapeptide. Predrag Sikiric’s team has carried out many investigations of its cytoprotective effects in different organs and tissues (1, 2)Their evidence indicates that BPC157 has potent cytoprotection in neural injury and gastrointestinal (GI) ulcers. Nevertheless.

全景超声生物显微镜和眼前节光学相干断层扫描在检测斜视患者内外直肌止端位置中的应用

目的:探讨应用全景超声生物显微镜(UBM)和眼前节光学相干断层扫描仪(AS-OCT)测量斜视患者角膜缘到水平眼外肌止端距离的可行性及准确性。方法:系列病例研究。术前应用全景UBM和AS-OCT测量斜视患者角膜缘到水平眼外肌止端距离,然后术中用卡尺测量角膜缘到水平眼外肌止端距离。采用Friedman检验、Mann-WhitneyU检验、Spearman相关性分析、Kendall一致性检验和Bland-Altman进行数据分析。结果:共纳入2018年3─9月在沈阳爱尔眼视光医院就诊的斜视患者73例,分析133条水平肌肉(72条外直肌、61条内直肌)。角膜缘到水平眼外肌止端的距离,在外直肌和内直肌中,UBM测量值分别为6.60(5.34~8.28)mm、5.41(4.16~7.48)mm,AS-OCT测量值分别为6.59(5.10~8.80)mm、5.17(3.44~7.41)mm,术中卡尺测量值分别为7.0(5.0~8.5)mm、5.0(3.5~7.0)mm。比较3种测量方法在外直肌和内直肌中的差异,除内直肌中UBM与术中卡尺测量差异有统计学意义外(P=0.017),余差异无统计学意义。Spearman相关分析显示外直肌中UBM、AS-OCT测量值分别与卡尺测量值存在强相关关系(r=0.656、0.608,均P<0.001),UBM测量值与AS-OCT测量值存在中等相关关系(r=0.530,P<0.001);内直肌中UBM测量值、AS-OCT测量值与卡尺测量值存在中等相关关系(r=0.597、0.458,均P<0.001),UBM测量值与AS-OCT测量值存在弱相关关系(r=0.379,P=0.003)。Kendall的非一致性检验和Bland-Altman提示3种测量方法间有良好的一致性。结论:全景UBM和AS-OCT可以准确测量初次斜视手术患者角膜缘到水平眼外肌止端的距离。

Microglial SIRPα Deletion Facilitates Synapse Loss in Preclinical Models of Neurodegeneration

Microglia,the principal immune cells in the brain,play a vital role in the development and homeostasis of the central nervous system[1,2].During early brain development,microglia-mediated synapse pruning contributes to eliminating excess synapses that are unnecessary in adulthood[3].Excessive microglia-mediated pruning in the adult brain is implicated in neurodegeneration-associated behav・ioral deficits[4,5].