Diagnostic Prospectives with Tau Protein and Imaging Techniques to Detect Development of Chronic Traumatic Encephalopathy

Brain damage sustained from repeated blows in boxing, wrestling, and other combat sports has serious physical and mental health consequences. The degenerative brain disease, chronic traumatic encephalopathy (CTE), presents clinically with memory loss, aggression, difficulty in rational thinking and other cognitive problems. This spectrum, which mimics Alzheimer’s disease, is diagnosed post-mortem through a brain biopsy in many professional athletes. However, little is known about the process of development and how to identify vulnerable individuals who may be on course for developing CTE. Boxing is a sport that has a severe toll on athletes’ health, primarily on their brain health and function. This review addresses the concerns of brain injury, describes the pathologies that manifest in multiple scales, e.g., molecular and cognitive, and also proposes possible diagnostic and prognostic markers to characterize the early onset of CTE along with the aim to identify a starting point for future precautions and interventions.

Effect of pesticides on phosphorylation of tau protein,and its influence on Alzheimer’s disease

Alzheimer’s disease(AD)is a progressive and neurodegenerative illness which results in alterations in cognitive development.It is characterized by loss/dysfunction of cholinergic neurons,and formation of amyloid plaques,and formation of neurofibrillary tangles,among other changes,due to hyperphosphorylation of tau-protein.Exposure to pesticides in humans occurs frequently due to contact with contaminated food,water,or particles.Organochlorines,organophosphates,carbamates,pyrethroids and neonicotinoids are associated with the most diagnosed incidents of severe cognitive impairment.The aim of this study was to determine the effects of these pesticides on the phosphorylation of tau protein,and its cognitive implications in the development of AD.It was found that exposure to pesticides increased the phosphorylation of tau protein at sites Ser198,Ser199,Ser202,Thr205,Ser396 and Ser404.Contact with these chemicals altered the enzymatic activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta,and protein phosphatase-2A.Moreover,it altered the expression of the microtubule associated protein tau gene,and changed levels of intracellular calcium.These changes affected tau protein phosphorylation and neuroinflammation,and also increased oxidative stress.In addition,the exposed subjects had poor level of performance in tests that involved evaluation of novelty,as test on verbal,non-verbal,spatial memory,attention,and problem-solving skills.

Tau protein,phosphorylated tau protein,and beta-amyloid 42 levels in patients with neurodegenerative diseases complicated by cognitive deficits A non-randomized,concurrent,case-control investigation

BACKGROUND： The differential diagnosis of many neurodegenerative disorders depends primarily on clinical symptoms together with imaging methods. Recently, increased importance has been placed on the use of biomarkers for diagnosing various neurodegenerative disorders. OBJECTIVE： To assess the feasibility of tau-protein, phosphorylated tau-protein, beta-amyloid 42 （Aβ42）, and 14-3-3 protein as biomarkers for diagnosing several neurodegenerative diseases complicated by cognitive deficits. DESIGN, TIME AND SETTING： A non-randomized, concurrent, case-control investigation was performed in three medical centers in the Czech Republic （Department of Neurology at the University Hospital in Hradec Kralove, Department of Neurology at the 2rd Medical Faculty, and the University Hospital Motol） between October 2000 and November 2006. PARTICIPANTS： Eighteen patients with probable AIzheimer＇s disease, 4 patients with Creutzfeldt-Jakob disease, 10 patients with frontotemporal dementia, 9 patients with clinically isolated syndrome suggestive of multiple sclerosis, and 7 patients with multiple sclerosis, as well as 38 race-, nationality-, and age-matched cognitively intact controls, were included in the study. Diagnoses were established based on the following criteria： the criteria for Alzheimer＇s disease proposed by the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer＇s Disease and Related Disorders Association, WHO criteria for Creutzfeldt-Jakob disease, Neary criteria for frontotemporal dementia, and McDonald＇s criteria for multiple sclerosis. All included patients were confirmed to suffer from various degrees of dementia. METHODS： Enzyme-linked immunosorbent assay was used to measure concentrations of tau-protein, phosphorylated tau-protein, and Aβ42 in cerebrospinal fluid （CSF） samples collected by standard lumbar puncture from each patient. Moreover, 14-3-3 protein was assessed by Western blot in CSF of Creutzfeldt-Jakob disease patients. Cognitive status was assessed using the Mini Mental Scale Examination （MMSE） in all subjects. MAIN OUTCOME MEASURES： Establishment of biomarkers with greatest specificity and sensitivity for the investigated disorders according to Receiver Operating Characteristic curves, which were based on values from patients and controls; correlation between concentrations of given biomarkers and demographic parameters, diagnosis, duration of disease, and level of cognitive deficit. RESULTS： Increased concentrations of total tau protein and phosphorylated tau protein, and decreased levels of Aβ42, in CSF of Alzheimer＇s disease patients reached the required sensitivity/specificity ratio of 80% or greater. A marked elevation in CSF concentrations of total tau protein showed even greater sensitivity than 14-3-3 protein in Creutzfeldt-Jakob disease. There was no association between selected biomarkers and frontotemporal dementia or multiple sclerosis. Phosphorylated tau-protein was the only biomarker that noticeably correlated with MMSE scores for Alzheimer＇s disease.CONCLUSION： Levels of total tau protein, phosphorylated tau protein, and A!342 in the CSF could differentiate patients with Alzheimer＇s disease and Creutzfeldt-Jakob disease from healthy controls and patients with other neurodegenerative disorders. The diversity of absolute values demonstrates the necessity to establish a specific standard for each laboratory.

Effect of erythropoietin combined with hypothermia on serum tau protein levels and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy

Although hypothermia therapy is effective to treat neonatal hypoxic-ischemic encephalopathy,many neonatal patients die or suffer from severe neurological dysfunction.Erythropoietin is considered one of the most promising neuroprotective agents.We hypothesized that erythropoietin combined with hypothermia will improve efficacy of neonatal hypoxic-ischemic encephalopathy treatment.In this study,41 neonates with moderate/severe hypoxic-ischemic encephalopathy were randomly divided into a control group（hypothermia alone for 72 hours,n = 20） and erythropoietin group（hypothermia ＋ erythropoietin 200 IU/kg for 10 days,n = 21）.Our results show that compared with the control group,serum tau protein levels were lower and neonatal behavioral neurological assessment scores higher in the erythropoietin group at 8 and 12 days.However,neurodevelopmental outcome was similar between the two groups at 9 months of age.These findings suggest that erythropoietin combined with hypothermia reduces serum tau protein levels and improves neonatal behavioral neurology outcome but does not affect long-term neurodevelopmental outcome.

Neurofibrillary tangles in Alzheimer＇s disease： elucidation of the molecular mechanism by immunohistochemistry and tau protein phospho-proteomics

As a key contributor to memory storage, the synapse is one of the earliest affected neuronal components in Alzheimer＇s disease （AD）. Under physiological conditions, the synaptic con- nections between neurons undergo activity-dependent func- tional and morphological re-organisation. This dynamic, ＇plastic＇ neural ability critically depends on the structural integrity of the synapse. Thus, proteins that are implicated in preserving the organisation and dynamics of synaptic connections, including microtubules of the cytoskeleton and associated proteins, have attracted much focus for their involvement in the malfunction- ing AD synapse.

Role of Notoginsenoside Rg1 in Improving Spatial Cognitive Ability and Lowering Phosphorylation Level of Tau Protein in AD Model Rats

[Objectives] To study the effects and mechanism of notoginsenoside Rg1 on the spatial learning and memory and phosphorylated tau protein in the AD( Alzheimer's Disease) model rat. [Methods]The AD model rat was replicated by injection of Aβ_(25-35) in the left lateral ventricles of SD rats. The low dose( 25 mg/kg),middle dose( 50 mg/kg) and high dose( 100 mg/kg) notoginsenoside Rg1 was used for intragastric administration,respectively,two times every day. After 4 weeks,the Morris water maze test was done to detect the learning and memory capacity,and the immunoblotting,immunohistochemical methods were used to detect the changes in the phosphorylation level and distribution of tau protein in hippocampus of the rats. [Results] After the intracerebroventricular injection of Aβ_(25-35),the learning and memory capacity of the model rats was significantly lower than the learning and memory capacity of the normal control rats. The immunoblotting test results showed that the phosphorylation level of tau protein threonine 231 site( Thr231) in hippocampus was significantly increased,and the nonphosphorylation level was significantly decreased. The morphological testing results showed that the phosphorylation level of tau protein Thr231 of AD model rats was increased markedly in region of DG,CA1 and CA3 of the hippocampus. The intervention of the middle dose notoginsenoside Rg1 could significantly improve the learning and memory capacity of the model rats in Morris water maze. The notoginsenoside Rg1 in three different doses could all reduce the phosphorylation level of tau protein Thr231 in the hippocampal DG,CA1,CA3 regions,and there were no significant differences among the three doses. [Conclusions]The notoginsenoside Rg1 could improve Aβ_(25-35)-induced spatial learning and memory impairment of the AD model rats,and decreased the phosphorylation level of tau protein in hippocampus.

Phosphorylation of tau protein over time in rats subjected to transient brain ischemia

Transient brain ischemia has been shown to induce hyperphosphorylation of the micro- tubule-associated protein tau. To further determine the mechanisms underlying these processes, we investigated the interaction between tau, glycogen synthase kinase （GSK）-313 and protein phos- phatase 2A. The results confirmed that tau protein was dephosphorylated during brain ischemia; in addition, the activity of GSK-3β was increased and the activity of protein phosphatase 2A was de- creased. After reperfusion, tau protein was hyperphosphorylated, the activity of GSK-3β was de- creased and the activity of protein phosphatase 2A remained low. Importantly, the interaction of tau with GSK-3β and protein phosphatase 2A was altered during ischemia and reperfusion. Lithium chloride could affect tau phosphorylation by regulating the interaction of tau with GSK-3β and pro- tein phosphatase 2A, and improve learning and memory ability of rats after transient brain ischemia. The present study demonstrated that it was the interaction of tau with GSK-3β and protein phos- phatase 2A, rather than their individual activities, that dominates the phosphorylation of tau in tran- sient brain ischemia. Hyperphosphorylated tau protein may play an important role in the evolution of brain injury in ischemic stroke. The neuroprotective effects of lithium chloride partly depend on the inhibition of tau phosphorylation during transient brain ischemia.

Neuroprotective effect of heat shock protein 70 Inhibition of Tau protein expression

BACKGROUND： Previous studies have shown that heat shock protein 70 （HSP70） has neuroprotective effects by decreasing phosphorylation of Tau protein, thereby reducing the expression of Tau protein and proper aggregation. OBJECTIVE： To observe and verify expressional changes of HSP70 and Tau in retinal ganglion cells following stretch injury to the right optic nerve in rats, and to determine the effect of heat stress pretreatment on HSP70 and Tau protein expressions. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Laboratory of Neurology Research Institute of the First Affiliated Hospital of Chongqing Medical University from March to June 2006. MATERIALS： Instant SABC immunohistochemistry kit, as well as mouse anti-HSP70 and rabbit anti-Tau polyclonal antibodies, were purchased from Wuhan Boster Bioengineering Limited, China. METHODS： A total of 57 male, Wistar rats were randomly assigned to 4 groups： control （n = 3）; 150-180 g stretch force was induced in the right optic nerves in stretch-only group （n = 18） to establish optic nerve stretch injury model; heat stress was applied to 18 animals in heat-stress treatment group; 18 rats in the heat-stress pretreatment plus stretch group were subjected to identical stretch injury as stretch-only group after 24-hour heat-stress pretreatment. According to sacrifice time, the groups were assigned to 6 subgroups at different time points of 4, 8, and 16 hours, and 1,3, and 5 days, with 3 rats in each subgroup. No treatment was performed in the control group except anesthesia. MAIN OUTCOME MEASURES： Morphological changes of optic nerves and retinal ganglion cells following stretch injury were observed by light microscopy following hematoxylin-eosin staining. HSP70 and Tau protein expression levels were observed in retinal ganglial cells from each group using im munohistochemistry. RESULTS： （1） Compared with the control group, morphological axonal and retinal ganglial cell changes, as well as a decreased number of retinal ganglial cells, were identified in the stretch-only group （P 〈 0.01）. Pathological damage in optical nerve and retinal ganglial cells were not remarkable in the heat-stress pretreatment plus stretch group, with no statistical difference in the number of retinal ganglial cells compared with the control group （P 〉 0.05）. （2） Compared with the control group significantly increased HSP70 expression in retinal ganglial cells occurred in the stretch-only, heat-stress treatment, and heat-stress pretreatment plus stretch groups （P 〈 0.05 or P 〈 0.01 ）. The peak of HSP70 expression was earlier in the heat-stress pretreatment plus stretch group compared with the stretch-only and heat-stress treatment groups, and was expressed over a longer period of time compared with the heat-stress treatment group. Compared with the control group, Tau expression in the retinal ganglial cells rapidly increased 4-16 hours following stretch injury in the stretch-only group （P 〈 0.05 or P 〈 0.01）, and obviously decreased in the heat-stress pretreatment plus stretch group （P 〈 0.05 or P 〈 0.01 ）. CONCLUSION： Tau expression increased following stretch injury, with an earlier expression peak than HSP70, which indicated that stretch injury-induced HSP70 expression was not strong or quick enough to sufficiently protect the nerve. A much more enhanced HSP70 expression, with an earlier peak and longer expression period, was observed in rats subjected to stretch injury following heat stress, which demonstrated that HSP70 exhibited neuroprotective functions by reducing abnormal aggregation of Tau.

Propofol can Protect Against the Impairment of Learning-memory Induced by Electroconvulsive Shock via Tau Protein Hyperphosphorylation in Depressed Rats

Objective To explore the possible neurophysiologic mechanisms of propofol and N-methyl-Daspartate(NMDA) receptor antagonist against learning-memory impairment of depressed rats without olfactory bulbs. Methods Models of depressed rats without olfactory bulbs were established. For the factorial design in analysis of variance, two intervention factors were included: electroconvulsive shock groups(with and without a course of electroconvulsive shock) and drug intervention groups [intraperotoneal(ip) injection of saline, NMDA receptor antagonist MK-801 and propofol. A total of 60 adult depressed rats without olfactory bulbs were randomly divided into 6 experimental groups(n=10 per group): ip injection of 5 ml saline; ip injection of 5 ml of 10 mg/kg MK-801; ip injection of 5 ml of 10 mg/kg MK-801 and a course of electroconvulsive shock; ip injection of 5 ml of 200 mg/kg propofol; ip injection of 5 ml of 200 mg/kg propofol and a course of electroconvulsive shock; and ip injection of 5 ml saline and a course of electroconvulsive shock. The learning-memory abilities of the rats was evaluated by the Morris water maze test. The content of glutamic acid in the hippocampus was detected by high-performance liquid chromatography. The expressions of p-AT8Ser202 in the hippocampus were determined by Western blot analysis. Results Propofol, MK-801 or electroconvulsive shock alone induced learning-memory impairment in depressed rats, as proven by extended evasive latency time and shortened space probe time. Glutamic acid content in the hippocampus of depressed rats was significantly up-regulated by electroconvulsive shock and down-regulated by propofol, but MK-801 had no significant effect on glutamic acid content. Levels ofphosphorylated Tau protein p-AT8Ser202 in the hippocampus was up-regulated by electroconvulsive shock but was reduced by propofol and MK-801 alone. Propofol prevented learning-memory impairment and reduced glutamic acid content and p-AT8Ser202 levels induced by electroconvulsive shock. Conclusion Electroconvulsive shock might reduce learning-memory impairment caused by protein Tau hyperphosphorylation in depressed rats by down-regulating glutamate content.

Impact of apolipoprotein E isoforms on sporadic Alzheimer's disease:beyond the role of amyloid beta

The impact of apolipoprotein E(ApoE)isoforms on sporadic Alzheimer's disease has long been studied;however,the influences of apolipoprotein E gene(APOE)on healthy and pathological human brains are not fully understood.ApoE exists as three common isoforms(ApoE2,ApoE3,and ApoE4),which differ in two amino acid residues.Traditionally,ApoE binds cholesterol and phospholipids and ApoE isoforms display diffe rent affinities for their receptors,lipids transport and distribution in the brain and periphery.The role of ApoE in the human depends on ApoE isoforms,brain regions,aging,and neural injury.APOE E4 is the strongest genetic risk factor for sporadic Alzheimer's disease,considering its role in influencing amyloid-beta metabolism.The exact mechanisms by which APOE gene variants may increase or decrease Alzheimer's disease risk are not fully understood,but APOE was also known to affect directly and indirectly tau-mediated neurodegeneration,lipids metabolism,neurovascular unit,and microglial function.Consistent with the biological function of ApoE,ApoE4 isoform significantly alte red signaling pathways associated with cholesterol homeostasis,transport,and myelination.Also,the rare protective APOE variants confirm that ApoE plays an important role in Alzheimer's disease pathogenesis.The objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer's disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE,brain function,and memory,from a molecular to a clinical level.APOE genotype also exerted a heterogeneous effect on clinical Alzheimer's disease phenotype and its outcomes.Not only in learning and memory but also in neuro psychiatric symptoms that occur in a premorbid condition.Cla rifying the relationships between Alzheimer's disease-related pathology with neuropsychiatric symptoms,particularly suicidal ideation in Alzheimer's disease patients,may be useful for elucidating also the underlying pathophysiological process and its prognosis.Also,the effects of anti-amyloid-beta drugs,recently approved for the treatment of Alzheimer's disease,could be influenced by the APOE genotype.

鼠李糖乳杆菌对老年小鼠术后海马区小胶质细胞激活及Tau蛋白磷酸化的影响

【目的】探讨术前益生菌鼠李糖乳杆菌(LGG)灌胃对麻醉手术老年小鼠海马区小胶质细胞及Tau磷酸化的影响。【方法】18月龄C57BL/6J小鼠30只随机分为3组,10只/组:对照组,麻醉手术组,麻醉手术+鼠李糖乳杆菌组。生理盐水/LGG 109CFU 150μL灌胃,每日1次,连续20 d后接受异氟醚麻醉+剖腹探查手术,术后12 h免疫荧光染色检测海马区小胶质细胞激活状态,ELISA检测IL-6的浓度变化,Western blot检测Tau蛋白磷酸化位点Tau-pS202/pT205和total Tau蛋白表达变化。【结果】对照组海马区小胶质细胞呈静息状态,炎症因子IL-6浓度为(82.08±12.07)pg/mL。与对照组相比,麻醉手术组海马区小胶质细胞活化增生,胞体变大,突起缩短变粗,炎症因子IL-6上升至(123.7±5.72)pg/mL(P=0.000),磷酸化Tau-pS202/pT205蛋白表达量也明显增加(P=0.002)。而与麻醉手术组相比,麻醉手术+LGG组海马区小胶质细胞增生肥大不明显,炎症因子IL-6分泌减少至(96.68±9.59)pg/mL(P=0.008),磷酸化Tau-pS202/pT205蛋白表达量明显下降(P=0.002)。而3组total Tau蛋白表达水平差异无统计学意义。【结论】术前服用益生菌鼠李糖乳杆菌减轻麻醉手术导致的老年小鼠海马区小胶质细胞活化、炎症因子分泌增加、以及Tau蛋白磷酸化水平增加。

超声引导下腹横肌平面麻醉对无张力疝修补术患者血清Tau蛋白的影响

目的:探讨无张力疝修补术患者采用超声引导下腹横肌平面麻醉(TAPB)的临床效果及对血清蛋白的影响。方法:选取2018年2月-2019年2月于柳州市人民医院行无张力疝修补术的患者94例作为研究对象,采用随机数字表法分为对照组和观察组,各47例。对照组进行全身麻醉,观察组采用超声引导下TAPB,比较两组麻醉效果及对血清蛋白[β淀粉样蛋白(Aβ)-42、Tau]。结果:术后1、3 d,观察组简易精神状态检查量表评分高于对照组,差异有统计学意义(P<0.05)。观察组术后20 min、1 h、8 h及24 h的疼痛评分低于对照组,差异有统计学意义(P<0.05)。术后7 d,观察组Aβ-42水平高于对照组,Tau蛋白及Tau/Aβ-42水平低于对照组,差异有统计学意义(P<0.05)。结论:将超声引导下TAPB应用在无张力疝修补术患者中,可降低术后血清Tau蛋白水平,有助于预防认知功能障碍。

血浆中tau蛋白磷酸化表达在多奈哌齐治疗阿尔茨海默病中的机制研究

目的基于血浆中tau蛋白磷酸化探讨多奈哌齐对阿尔茨海默病(AD)的保护机制。方法2019年1月至2022年7月从齐齐哈尔市第一医院神经内科招募了两组参与者作为样本。在第一组样本中包括58名轻度至重度AD患者和20名健康老年对照组;另一组样本包括37名轻度至中度AD患者的样本,其中18名患者接受了24周的多奈哌齐治疗,19名患者接受了24周安慰剂治疗。从患者的血液标本中提取神经元衍生的细胞外囊泡(EV),采用酶联免疫吸附分析试剂盒对β淀粉样蛋白42(Aβ_(42))、P-T181-tau、P-S396-tau、总tau蛋白(t-tau)、神经颗粒蛋白(NRGN)水平进行分析。结果与对照组相比,AD患者的EV中Aβ_(42)、t-tau、P-T181-tau、P-S396-tau水平显著升高(P<0.05),NRGN水平显著降低(P<0.05)。在AD患者中,t-tau、NRGN和沉默转录因子(REST)的EV水平与简易智力状态检查量表(MMSE)和阿尔茨海默病合作研究–日常生活活动量表(ADCS-ADL)评分呈负相关(P<0.05),并与阿尔茨海默病评估量表–认知子量表的14项扩展版本(ADAS-cog+)评分呈正相关(P<0.05)。在为期24周的治疗期间,与安慰剂组患者相比,多奈哌齐组患者血浆中Aβ_(42)、t-tau、P-T181-tau和P-S396-tau的表达水平(EV水平)从基线水平到第24周结束时均呈显著降低趋势(P<0.05)。结论轻重度AD患者血浆EV中Aβ_(42)、t-tau、P-T181-tau和P-S393-tau水平升高。t-tau、NRGN和REST的水平增加与认知功能和生活能力的下降相关。多奈哌齐治疗可使轻中度AD患者血浆中t-tau、P-T181-tau和P-S396-tau的表达水平降低。

基于^(18)F-Florzolotau PET显像评估阿尔茨海默病脑内tau蛋白异常沉积

目的探讨新一代tau PET显像剂18F-Florzolotau在阿尔茨海默病(AD)不同发展阶段中的应用价值。资料与方法回顾性纳入2020年2月—2022年1月复旦大学附属华山医院β-淀粉样蛋白阳性的25例轻度认知功能障碍(MCI)与61例AD,患者均行18F-Florzolotau PET脑显像,并收集相关人口统计学与临床资料。使用SPM双样本t检验比较两组患者预处理后的18F-Florzolotau PET图像,以显著差异(P<0.001)脑区为感兴趣区提取标准化摄取值比值(SUVR);同时利用尺度亚轮廓/主成分分析模型分别建立MCI、AD的tau蛋白异常沉积相关模式(MCItauRP、ADtauRP)并计算对应的表达值。采用受试者工作特征曲线评价MCItauRP、ADtauRP表达值以及SUVR的分类性能。结果AD组与MCI组患者相比,主要在双侧颞顶叶脑区tau蛋白异常沉积增加(P<0.001),此差异脑区感兴趣区内AD组SUVR高于MCI组(Z=-3.164,P<0.001);AD组与MCI组患者各MCItauRP、ADtauRP表达值差异有统计学意义(t=3.72,Z=-3.51;P均<0.001),且AD组患者表达值均高于MCI组;MCItauRP、ADtauRP表达值以及SUVR鉴别AD与MCI的准确度分别为61.63%、65.12%和65.12%,敏感度分别为88.00%、96.00%和100.00%,特异度分别为50.82%、52.46%和50.82%。结论新一代tau PET能够检测及区分AD、MCI患者脑内tau蛋白沉积,但分类准确度不高,未来需要进一步寻找更加理想的分析方法。

极长链饱和脂肪酸对人神经母细胞瘤细胞Tau蛋白磷酸化及膜流动性的影响

目的观察极长链饱和脂肪酸对人神经母细胞瘤细胞SH-SY5Y Tau蛋白磷酸化和膜流动性的影响,探讨其在阿尔茨海默病(AD)发病中的作用。方法取对数生长期的人神经母细胞瘤细胞SH-SY5Y,随机分为对照组、C220组、C240组,对照组细胞常规培养,C220组、C240组细胞分别加入含10μmol·L^(-1)极长链饱和脂肪酸C220、C240的培养液,培养24 h后收集细胞,采用Western blot法检测各组细胞中总Tau蛋白、丝氨酸396位点磷酸化Tau蛋白(p-Tau-ser396)、糖原合成酶激酶3β(GSK-3β)及GSK-3β丝氨酸9位点磷酸化蛋白(p-GSK-3β-Ser9)的表达水平;采用硫代巴比妥酸法测定各组细胞中丙二醛(MDA)水平;并采用荧光漂白恢复技术测定细胞膜荧光恢复率和扩散系数,评价细胞膜流动性。结果3组SH-SY5Y细胞总Tau蛋白水平比较差异无统计学意义(F=1.807,P>0.05)。3组SH-SY5Y细胞p-Tau-ser396水平比较差异有统计学意义(F=18.397,P<0.05);其中C220组和C240组SH-SY5Y细胞p-Tau-ser396水平显著高于对照组(P<0.05),C240组SH-SY5Y细胞p-Tau-ser396水平显著高于C220组(P<0.05)。3组SH-SY5Y细胞GSK-3β蛋白水平比较差异无统计学意义(F=0.351,P>0.05)。3组SH-SY5Y细胞p-GSK-3β-Ser9水平比较差异有统计学意义(F=13.330,P<0.05);其中C220组、C240组SH-SY5Y细胞p-GSK-3β-ser9水平显著低于对照组(P<0.05),C220组与C240组SH-SY5Y细胞p-GSK-3β-ser9水平比较差异无统计学意义(P>0.05)。C240组SH-SY5Y细胞MDA水平显著高于对照组和C220组(P<0.05);对照组与C220组SH-SY5Y细胞MDA水平比较差异无统计学意义(P>0.05)。对照组、C220组、C240组SH-SY5Y细胞的荧光恢复率和扩散系数有降低趋势,但3组SH-SY5Y细胞的荧光恢复率和扩散系数比较差异无统计学意义(F=3.891、3.649,P>0.05)。结论极长链饱和脂肪酸C220、C240可促进Tau蛋白过度磷酸化,诱导细胞氧化损伤,对细胞膜流动性也有降低趋势,极长链饱和脂肪酸可能是引起AD发病的因素之一。

针刺治疗Tau蛋白信号通路机制的研究进展

随着老龄化增速的不断加快,阿尔茨海默病(Alzheimer′s disease,AD)作为一种以老年人为多发群体的大脑细胞退化性疾病,逐渐引起社会关注。它具有让个体的思维认知和独立日常活动能力下降的特征,由于它的发病率不断增高,社会各界所面临的研究和治疗压力也愈加沉重。目前关于AD发病机理的研究仍在不断地深入和完善中,学术界从多个方向入手,提出了几类假说,其中就包括Tau蛋白过度磷酸化。近些年,中医药在Tau蛋白机制的研究中取得了较大的进展,这也为AD的防治工作做出了巨大贡献。文章通过了解针刺影响Tau蛋白信号通路的最新研究进展,结合近五年针刺和相关通路的研究成果,总结出Tau蛋白信号通路的运作机制,为后期的研究和治疗提供思路。

基于Tau蛋白磷酸化探讨中医药干预阿尔茨海默病的研究进展

阿尔茨海默病(Alzheimer’s Disease,AD)是一种以进行性认知功能障碍和记忆减退为主要特征的神经退行性疾病,Tau蛋白过度磷酸化是该病的主要发病机制之一。Tau蛋白是主要分布于中枢神经系统神经元轴突的微管相关蛋白,其过度磷酸化则丧失与微管结合的能力,造成微管解聚、轴突转运障碍,形成Tau聚集体,进而引起神经细胞的凋亡,导致AD的发生。研究表明中医药可以通过多通路、多靶点调控Tau蛋白磷酸化来干预AD。主要以Tau蛋白磷酸化为切入点,对干预AD中医药的种类和作用机制进行总结,以期为中医药防治AD的研究提供参考。

不同神经阻滞麻醉方案对胃癌根治患者术后疼痛、认知功能及血清Aβ-42、IL-6、tau-181蛋白影响

目的 探讨不同神经阻滞麻醉方案[椎旁神经阻滞术(TPVB)和星状神经节阻滞术(SGB)]对胃癌根治患者术后疼痛、认知功能及血清β淀粉样蛋白-42(Aβ-42)、白细胞介素-6(IL-6)、tau-181蛋白影响。方法 选取河北北方学院附属第一医院2020年1月至2023年1月收治的择期行腹腔镜胃癌根治术的患者120例为研究对象,按照随机数字表法分为TPVB组和SGB组,各60例。两组术中全麻方式相同,TPVB组在麻醉诱导前进行椎旁神经阻滞术,SGB组在麻醉诱导前进行星状神经节阻滞术。分别采用视觉模拟评分法(VAS)及蒙特利尔认知评估量表(MoCA)评估患者疼痛情况及认知功能;监测两组术后不同时间点疼痛变化情况,比较两组术前、术后1、3 d的认知功能及血清Aβ-42、IL-6、tau-181蛋白水平变化。结果 两组术后1、6、12、24 h的VAS评分差异均无统计学意义(t=1.183、1.325、0.397、0.611,P>0.05);术后1、3 d两组MoCA量表评分比较为TPVB组评分低于SGB组,差异均有统计学意义(t=2.281、3.218,P<0.05);术后1、3 d两组血清指标比较均为TPVB组Aβ-42、IL-6及tau-181蛋白水平高于SGB组,差异均有统计学意义(t=2.065、2.122、2.558、2.167、2.515、2.596,P<0.05)。结论 TPVB及SGB两种神经阻滞麻醉方案对胃癌根治患者术后镇痛均有良好的效果,但SGB比TPVB在减轻患者炎症反应及认知功能的改善方面更具优势。

血清BDNF、VitB_(12)、Tau蛋白水平与缺氧缺血性脑病早产儿脑神经发育的相关性分析

目的探究血清脑源性神经营养因子(BDNF)、维生素B_(12)(VitB_(12))、Tau蛋白水平与缺氧缺血性脑病早产儿脑神经发育的相关性。方法选取2020年1月至2023年6月收治的80例缺氧缺血性脑病早产儿作为患儿组,另选取同期80例健康新生儿作为健康组。检测新生儿血清BDNF、VitB_(12)、Tau蛋白水平,评估新生儿神经行为评定法(NBNA)评分,分析血清BDNF、VitB_(12)、Tau蛋白水平与NBNA评分的相关性。结果出生后3 d,患儿组的BDNF、VitB_(12)水平及NBNA评分低于健康组,Tau蛋白水平高于健康组,差异具有统计学意义(P<0.05)。CT检查结果显示,轻度组33例,中度组35例,重度组12例;出生后3 d,不同疾病程度患儿的BDNF、VitB_(12)、Tau蛋白水平及NBNA评分比较,差异具有统计学意义(P<0.05)。患儿组出生后14 d的BDNF、VitB_(12)水平及NBNA评分高于出生后3 d,Tau蛋白水平低于出生后3 d,差异具有统计学意义(P<0.05)。Pearson相关性分析结果显示,BDNF、VitB_(12)水平与NBNA评分呈正相关(r=0.473、0.435,P<0.05);Tau蛋白水平与NBNA评分呈负相关(r=-0.411,P<0.05)。结论血清BDNF、VitB_(12)水平与缺氧缺血性脑病早产儿脑神经发育呈正相关,Tau蛋白水平与缺氧缺血性脑病早产儿脑神经发育呈负相关。

高原鼠兔、高原鼢鼠肠道菌群对低压低氧环境下大鼠海马组织Aβ、Tau及BDNF蛋白的影响

为了探究暴露低压低氧不同时间以及移植高原鼠兔、高原鼢鼠肠道菌群后暴露低压低氧环境是否会影响SD大鼠海马组织β淀粉样蛋白(beta-amyloid protein, Aβ)、tau及脑源性神经营养因子(brain-derived neurotrophic factor, BDNF)的表达水平,首先将SD大鼠随机分为常氧组、低压低氧组和低压低氧处理组,低压低氧组根据暴露低压低氧时间又分为第1、3、7、15、28天组,低压低氧处理组则根据处理因素分为低压低氧对照组、低压低氧+抗生素处理组、低压低氧+抗生素+鼢鼠菌处理组、低压低氧+抗生素+鼠兔菌处理组、低压低氧+抗生素+SD大鼠菌处理组(10只/组),共11组;然后采用尼氏染色观察常氧组和低压低氧组海马组织神经细胞的形态变化,采用Western-blot检测各组Aβ、tau及BDNF蛋白表达水平。结果显示,与常氧组相比,低压低氧组从第3天开始海马组织CA1区的神经细胞排列疏松紊乱,细胞核固缩明显,并具有时间依赖性;Aβ、tau蛋白水平分别从低压低氧暴露第7天、3天开始显著升高,并随低压低氧暴露时间的延长进一步升高,其中以tau蛋白升高尤为明显;BDNF蛋白在低压低氧暴露初期显著升高,而后随低压低氧暴露时间的延长逐渐降低,与Aβ和tau蛋白水平呈现显著的负相关。此外,与抗生素处理组相比,在低压低氧环境下,移植高原鼠兔肠道菌群的大鼠海马组织中Aβ、tau蛋白的表达显著下降, BDNF的表达明显升高。实验结果初步表明,低压低氧可上调大鼠海马组织Aβ、tau蛋白表达,下调BDNF蛋白表达;肠道菌群移植可上调低压低氧环境下大鼠海马组织BDNF蛋白的表达,同时影响Aβ、tau蛋白的表达,其中高原鼠兔肠道菌群移植大鼠海马组织中的Aβ、tau蛋白水平被下调,高原鼢鼠肠道菌群移植大鼠海马组织中的tau蛋白水平被上调, Aβ蛋白水平被下调。