Tau蛋白与认知功能

Tau蛋白为正常的生理蛋白,其高度磷酸化对认知功能有影响.围术期存在多种因素可以通过蛋白激酶和蛋白磷酸酶相对活性失衡引起tau的磷酸化,从而影响术后认知功能.     

Tau蛋白与认知功能

Tau蛋白为正常的生理蛋白，其高度磷酸化对认知功能有影响。围术期存在多种因素可以通过蛋白激酶和蛋白磷酸酶相对活性失衡引起tau的磷酸化，从而影响术后认知功能。     

全凭静脉麻醉老龄大鼠海马tau蛋白磷酸化水平与认知功能的关系

目的 探讨咪唑安定、芬太尼、丙泊酚联用对老龄大鼠认知功能的影响以及这种影响是否与海马tau蛋白磷酸化水平有关.方法 雄性18月龄SD大鼠40只,随机分成全麻组和对照组,每组20只.每组分别于处理后第1和第7天各断头处死10只,HE染色光镜下观察海马神经元结构,免疫组化染色法检测海马tall蛋白Thr231和Ser404位点磷酸化蛋白的表达水平.其中后处死大鼠于处理后第1周行水迷宫实验.结果 处理后第1天,全麻组大鼠寻找平台的时间明显长于对照组(P＜0.01),但第2～7天与对照组比较差异无统计学意义.处理后第1天,全麻组海马tau蛋白Thr231位点的磷酸化水平高于对照组(P＜0.05).第7天,两组Thr231、Ser404位点的磷酸化水平差异无统计学意义.光镜下各组大鼠海马神经元结构未见明显异常.结论 咪唑安定、芬太尼、丙泊酚联用可引起老龄大鼠麻醉后第1天出现短暂的认知功能减退,海马tau蛋白Thr231位点的过度磷酸化可能与其有关.     

小胶质细胞在病理性Tau蛋白所致认知功能损害中的作用

Tau蛋白过度磷酸化形成的神经元纤维缠结(neurofibrillary tangle,NFT)被认为是引起认知功能损害的重要原因之一。过度磷酸化Tau蛋白以多种形式存在于中枢神经系统,对神经元产生毒性作用,并激活小胶质细胞产生免疫应答反应。文章探讨了病理性Tau蛋白中枢神经毒性作用,分析了小胶质细胞与病理性Tau蛋白相互作用在认知功能损害中所扮演的角色,阐述了通过诱导小胶质细胞分化方向调控分化后小胶质细胞分泌因子,干预病理性Tau蛋白所致的认知功能损害。     

黄芪多糖对肝叶部分切除小鼠术后认知功能及p38MAPK磷酸化的影响

目的探讨黄芪多糖对肝叶部分切除小鼠术后认知功能及p38MAPK磷酸化的影响。方法老年雄性昆明小鼠随机分为假手术组(S组)、手术组(O组)和黄芪多糖+手术组(A组)。术后1、3、7d,采用Morris水迷宫检测小鼠学习认知功能;采用Western blot技术检测小鼠海马区p38MAPK磷酸化水平。结果术后3d和7d,与S组比较,O组潜伏期明显延长(P0.01),穿台次数明显减少(P0.01或P0.05),在目标象限停留时间明显缩短(P0.01);与O组比较,A组潜伏期明显缩短,穿台次数明显增加,在目标象限停留时间明显延长(P0.05)。术后1、3、7d,O组p38MAPK磷酸化水平明显升高(P0.05);与O组比较,A组p38MAPK磷酸化水平明显下降(P0.05或P0.01)。术后1、3、7d各组p38MAPK蛋白表达总水平差异无统计学意义。结论黄芪多糖能够明显改善肝叶部分切除小鼠术后认知功能障碍,其机制可能与其抑制p38MAPK蛋白异常磷酸化有关。     

髋关节置换术老年患者术后谵妄与术前脑脊液β淀粉样蛋白-42和Tau蛋白的关系

目的 研究髋关节置换术老年患者术后谵妄(POD)与术前脑脊液β淀粉样蛋白(Aβ)-42、Tau及磷酸化Tau(pTau)水平的关系.方法 在蛛网膜下腔麻醉下行全髋关节置换术、ASA Ⅰ或Ⅱ级、年龄65～90岁的老年患者82例,术前应用简易精神状态量表(MMSE)对认知功能进行评定,术后根据谵妄评定法(CAM)将患者分为POD和非POD组.检测术前脑脊液Aβ-42、Tau及pTau水平,记录并分析围术期的相关危险因素.结果 髋关节置换术老年患者POD发生率为36.6％,其中年龄及术前认知功能水平为POD的高危因素(P＜0.05).与非POD组比较,POD组患者术前脑脊液中pTau明显升高,而Aβ-42降低(P＜0.05).结论 术前脑脊液中pTau及Aβ-42水平与POD发生相关,可以作为预测POD的指标.     

异丙酚麻醉对电休克诱发抑郁大鼠海马Tau蛋白过度磷酸化的影响

目的 探讨异丙酚麻醉对电休克诱发抑郁大鼠海马Tau蛋白过度磷酸化的影响.方法 选取Open-field测试总分为30～120分的雌性WKY大鼠32只,24周龄,体重200～250 g,采用随机数字表法,将其随机分为4组(n=8):对照组(C组)、异丙酚组(P组)、电休克组(E组)和异丙酚+电休克组(PE组).C组腹腔注射生理盐水5ml;P组腹腔注射100 mg/kg异丙酚5ml;E组腹腔注射生理盐水5ml,15 min后施行电休克治疗;PE组腹腔注射100 mg/kg异丙酚5ml,15 min后施行电休克治疗.电休克治疗结束24h时,采用Morris水迷宫测定大鼠认识功能.认知功能测试完毕6h时,处死大鼠,取海马组织,检测磷酸化Tau蛋白的表达.结果 与C组比较,P组、E组和PE组逃避潜伏期延长,游泳时间缩短,P组海马磷酸化Tau蛋白表达下调,E组海马磷酸化Tau蛋白表达上调(P＜0.05),PE组海马磷酸化Tau蛋白表达差异无统计学意义(P＞0.05);与E组比较,PE组逃避潜伏期缩短,游泳时间延长,海马磷酸化Tau蛋白表达下调(P＜0.05).结论 异丙酚麻醉改善电休克诱发抑郁大鼠认知功能障碍的机制与抑制海马Tau蛋白过度磷酸化有关.     

神经炎症反应和中枢神经退行性变与老年患者术后认知功能障碍

背景 术后认知功能障碍(postoperative cognitive dysfunction,POCD)是麻醉手术后尤其是老年患者麻醉术后常见的神经系统并发症. 目的 现在从神经系统炎症反应和中枢功能减退等对POCD的影响作一综述,为防治POCD的发生和发展提供有效的方法. 内容 介绍POCD的发生与炎症反应、磷酸腺苷活化蛋白激酶(adenosine monophosphate activated protein kinase,AMPK)信号通路的改变、Tau蛋白、β淀粉样蛋白的改变(β-amyloid,A β)、中枢胆碱能系统功能减退等的关系.趋向 更深入研究POCD发生的病理机制,从POCD的发生原理上为预防POCD的发生和获得有效的治疗提供新思路.     

去势雌性大鼠海马区Tau蛋白Alzheimer样磷酸化的变化

目的探讨去势雌性大鼠海马区Tau蛋白Alzheimer样磷酸化的变化。方法建立大鼠双侧卵巢切除(OVX)模型,分别于术后1、2、3、4和8周取大鼠海马组织,WesternBlot检测Tau蛋白的磷酸化程度。结果与假手术组相比,OVX组去势后4和8周在海马区的PHF1位点异常磷酸化Tau蛋白显著升高(P<0.01),而相同时间点和相同区域的Tau1位点非磷酸化Tau蛋白的水平显著降低(P<0.01)。结论雌激素缺乏可导致雌性大鼠海马区Tau蛋白Alzheimer样过度磷酸化。     

艾司氯胺酮对术后认知功能障碍老龄大鼠海马神经元程序性坏死的影响

目的评价艾司氯胺酮对术后认知功能障碍老龄大鼠海马神经元程序性坏死的影响。方法 SPF级健康雄性SD大鼠120只, 月龄22月, 体质量550～600 g, 采用随机数字表法分为4组(n=30):对照组(C组)、术后认知功能障碍组(P组)、术后认知功能障碍+艾司氯胺酮组(PE组)和艾司氯胺酮组(CE组)。P组和PE组大鼠在七氟烷麻醉下接受剖腹探查术, 术毕分别腹腔注射艾司氯胺酮10 mg/kg和等量0.9%氯化钠注射液, 1次/d, 连续6 d。CE组和C组不给予麻醉手术处理, 分别腹腔注射艾司氯胺酮10 mg/kg和等量0.9%氯化钠注射液, 1次/d, 连续6 d。4组大鼠于术后7 d时行Morris水迷宫实验, 记录逃避潜伏期、穿越原平台位置次数和原平台所在象限停留时间;水迷宫实验结束后, 处死大鼠取海马组织, 采用流式细胞术测定海马神经元程序性坏死率和胞浆Ca2+浓度;采用Western blot法检测混合谱系激酶结构域样蛋白(MLKL)、磷酸化MLKL(p-MLKL)、受体相互作用蛋白3(RIPK3)、磷酸化RIPK3(p-RIPK3)、RIPK1和磷酸化RIPK1(p-RIP...     

Tau is hyperphosphorylated at multiple sites in mouse brain in vivo after streptozotocin-induced insulin deficiency

Deficient signaling by insulin, as occurs in diabetes, is associated with impaired brain function, and diabetes is associated with an increased prevalence of Alzheimer's disease. One of the hallmark pathological characteristics of Alzheimer's disease is the presence of neurofibrillary tangles containing hyperphosphorylated tau, a microtubule-associated protein. Therefore, we tested the hypothesis that insulin depletion caused by administration of streptozotocin may cause tau hyperphosphorylation in mouse brain by using site-specific phosphorylation-dependent tau antibodies to obtain precise identification of the phosphorylation of tau on individual residues. A massive (fivefold average increase) and widespread at multiple residues (detected with eight different phosphorylation-dependent tau antibodies) increase in the phosphorylation of tau was found in mouse cerebral cortex and hippocampus within 3 days of insulin depletion by streptozotocin treatment. This hyperphosphorylation of tau at some sites was rapidly reversible by peripheral insulin administration. Examination of several kinases that phosphorylate tau indicated that they were unlikely to account for the widespread hyperphosphorylation of tau caused by streptozotocin treatment, but there was a large decrease in mouse brain protein phosphatase 2A activity, which is known to mediate tau phosphorylation. These results show that insulin deficiency causes rapid and large increases in tau phosphorylation, a condition that could prime tau for the neuropathology of Alzheimer's disease, thereby contributing to the increased susceptibility to Alzheimer's disease caused by diabetes.     

Peripheral hyperinsulinemia promotes tau phosphorylation in vivo

Cerebral insulin receptors play an important role in regulation of energy homeostasis and development of neurodegeneration. Accordingly, type 2 diabetes characterized by insulin resistance is associated with an increased risk of developing Alzheimer's disease. Formation of neurofibrillary tangles, which contain hyperphosphorylated tau, represents a key step in the pathogenesis of neurodegenerative diseases. Here, we directly addressed whether peripheral hyperinsulinemia as one feature of type 2 diabetes can alter in vivo cerebral insulin signaling and tau phosphorylation. Peripheral insulin stimulation rapidly increased insulin receptor tyrosine phosphorylation, mitogen-activated protein kinase and phosphatidylinositol (PI) 3-kinase pathway activation, and dose-dependent tau phosphorylation at Ser202 in the central nervous system. Phospho-FoxO1 and PI-3,4,5-phosphate immunostainings of brains from insulin-stimulated mice showed neuronal staining throughout the brain, not restricted to brain areas without functional blood-brain barrier. Importantly, in insulin-stimulated neuronal/brain-specific insulin receptor knockout mice, cerebral insulin receptor signaling and tau phosphorylation were completely abolished. Thus, peripherally injected insulin directly targets the brain and causes rapid cerebral insulin receptor signal transduction and site-specific tau phosphorylation in vivo, revealing new insights into the linkage of type 2 diabetes and neurodegeneration.     

Widespread neuronal and glial hyperphosphorylated tau deposition in ALS with cognitive impairment

Although the biological basis of frontotemporal syndromes associated with amyotrophic lateral sclerosis (ALS) is considered to be altered metabolism of TDP-43, in ALS with cognitive impairment (ALSci) the metabolism of tau protein is also altered. This includes neuronal hyperphosphorylation (pThr(175)). Using novel polyclonal phospho-tau antibodies (pSer(208, 210), pThr(217) and pThr(175)) and antibodies directed against PHF tau (pSer(202)), TDP-43 or ubiquitin, we characterized tau deposition in ALS and ALSci. In ALS, we observed pThr(175) tau immunoreactive intraneuronal and neuritic aggregates throughout the amygdala and entorhinal cortex. In ALSci, this extended to the anterior cingulate gyrus, superior frontal cortex and substantia nigra. The pThr(217) antibody detected widespread astrocytic tau deposition, including punctuate or fibrillary aggregates, or intensely immunoreactive tufted astrocytes in the superior frontal cortex, anterior cingulate gyrus, entorhinal cortex, amygdala and basal ganglia of ALS. In ALSci, a similar but more widely distributed pThr(217) pathology was observed. There was no correlation between the extent of pathological tau deposition and TDP-43 pathology, although nuclear TDP-43 immunoreactivity was absent in neurons with tau pathology. In conclusion, ALSci is unique in possessing both tau and TDP-43 pathology. The presence of widespread astrocytic tau pathology suggests that ALSci may initially be characterized by astrocytic pathology.     

乌司他丁后处理对肝切除老年大鼠学习记忆功能的影响及机制研究

目的观察乌司他丁（UTI）后处理对肝部分切除术（PH）老年大鼠学习记忆能力的影响并探讨其作用机制。 方法选择健康雄性无特定病原体SPF级C57BL/6J大鼠36只,18月龄,体质量27~36 g。按照随机数字表法将大鼠分为3组：对照组（C组）、肝部分切除术组（PH组）和UTI后处理组（UTI组）,每组12只。UTI组大鼠术毕苏醒即刻经腹腔注射UTI 50 000 U/kg,连续注射7 d,C组和PH组大鼠连续7 d每日腹腔注射等量0.9%氯化钠溶液。3组大鼠于末次给药结束后24 h均进行Morris水迷宫试验和旷场实验等行为学测试,测试完毕后处死大鼠,立即取海马组织冻存备用,采用ELISA法检测海马组织炎性因子IL-1、IL-6、TNF-α水平,Western blotting法检测海马组织Amlyoid-β蛋白、tau蛋白、磷酸化tau-Ser396蛋白的表达。 结果与C组和UTI组比较,PH组大鼠第3、4天的逃避潜伏期、游泳距离均延长（F=11.783、72.141、70.807,均P<0.001）,探索时间、穿越次数均缩短（F=143.244、32.428,均P<0.001）,中央区探索时间、跨格次数、旷场直立次数均缩短（F=76.232、105.990、17.477,均P<0.001）;海马组织炎症因子TNF-α、IL-6、IL-1的浓度均增加（F=395.545、1 124.503、474.526,均P<0.001）,海马组织tau蛋白、磷酸化tau-Ser396蛋白、Amlyoid-β蛋白表达均增加（F=285.764、307.440、557.347,均P<0.001）。 结论UTI可改善PH后老年大鼠的学习记忆能力,其机制可能与UTI抑制海马细胞炎症及Amlyoid-β蛋白、tau蛋白、磷酸化tau-Ser396蛋白的表达有关。     

脾切除术对大鼠海马tau表达的影响

目的 评价脾切除术对大鼠海马tau表达的影响.方法 SD大鼠105只,随机分为3组,正常对照组(A组,n=15)不给予任何处理,麻醉组(B组,n=45)仅吸入1.5%异氟醚2 h,手术+麻醉组(C组,n=45)吸入1.5%异氟醚(吸入2 h)麻醉下实施脾切除术.B组和C组分别于麻醉后或术后1、3、7 d时处死15只大鼠,取海马组织,测定海马IL-1β mRNA、TNF-α mRNA、IL-1β、TNF-α、总tau、苏氨酸第205位点磷酸化tau(pT205 tau)、丝氨酸第396位点磷酸化tau(pS396 tau)、总糖原合成酶-3β(GSK-3β)和磷酸化GSK-3β(p-GSK-3β)的表达水平.结果 与A组比较,B组各时点IL-1β mRNA、TNF-α mRNA、IL-1β、TNF-α、总tau、pT205 tau、pS396 tau、GSK-3β和p-GSK-3β的表达水平差异无统计学意义(P＞0.05),C组术后IL-1βmRNA、TNF-α mRNA、IL-1β、pT205 tau和pS396 tau的表达上调,p-GSK-3β表达下调(P＜0.05或0.01).结论 手术创伤可导致大鼠海马tau磷酸化,其机制与手术创伤诱发炎性反应,从而激活GSK-3β有关.     

麻醉与阿尔茨海默病关系的研究进展

阿尔茨海默病是一种进行性中枢神经系统退行性疾病,研究者们发现全身麻醉在解除患者痛苦保证手术稳定进行的同时,也可能与阿尔茨海默病之间存在一定的潜在关系。其可能的机制包括钙离子调节失调、D淀粉样肽的沉积以及tau蛋白过度磷酸化。目前已有多项研究证实了吸入麻醉药可以产生阿尔茨海默病相关病理变化,但静脉麻醉药是否有类似作用尚存在争议。其他围手术期因素也可能成为其危险因素。本文对麻醉与阿尔茨海默病的关系及其机制以及可能的危险因素的研究现状进行综述。     

Insulin Action in Brain Regulates Systemic Metabolism and Brain Function

Insulin receptors, as well as IGF-1 receptors and their postreceptor signaling partners, are distributed throughout the brain. Insulin acts on these receptors to modulate peripheral metabolism, including regulation of appetite, reproductive function, body temperature, white fat mass, hepatic glucose output, and response to hypoglycemia. Insulin signaling also modulates neurotransmitter channel activity, brain cholesterol synthesis, and mitochondrial function. Disruption of insulin action in the brain leads to impairment of neuronal function and synaptogenesis. In addition, insulin signaling modulates phosphorylation of tau protein, an early component in the development of Alzheimer disease. Thus, alterations in insulin action in the brain can contribute to metabolic syndrome, and the development of mood disorders and neurodegenerative diseases.