An amyloid β42-dependent deficit in anandamide mobilization is associated with cognitive dysfunction in Alzheimer's disease

The endocannabinoids and their attending cannabinoid (CB)(1) receptors have been implicated in the control of cognition, but their possible roles in dementias are still unclear. In the present study, we used liquid chromatography/mass spectrometry to conduct an endocannabinoid-targeted lipidomic analysis of postmortem brain samples from 38 Alzheimer's disease (AD) patients and 17 control subjects, matched for age and postmortem interval. The analysis revealed that midfrontal and temporal cortex tissue from AD patients contains, relative to control subjects, significantly lower levels of the endocannabinoid anandamide and its precursor 1-stearoyl, 2-docosahexaenoyl-sn-glycero-phosphoethanolamine-N-arachidonoyl (NArPE). No such difference was observed with the endocannabinoid 2-arachidonoyl-sn-glycerol or 15 additional lipid species. In AD patients, but not in control subjects, statistically detectable positive correlations were found between (1) anandamide content in midfrontal cortex and scores of the Kendrick's Digit Copy test (p = 0.004, r = 0.81; n = 10), which measures speed of information processing; and (2) anandamide content in temporal cortex and scores of the Boston Naming test (p = 0.027, r = 0.52; n = 18), which assesses language facility. Furthermore, anandamide and NArPE levels in midfrontal cortex of the study subjects inversely correlated with levels of the neurotoxic amyloid peptide, amyloid β-protein (Aβ)(42), while showing no association with Aβ(40) levels, amyloid plaque load or tau protein phosphorylation. Finally, high endogenous levels of Aβ(42) in Swedish mutant form of amyloid precursor protein (APP(SWE))/Neuro-2a cells directly reduced anandamide and NArPE concentrations in cells lysates. The results suggest that an Aβ(42)-dependent impairment in brain anandamide mobilization contributes to cognitive dysfunction in AD.     

Pseudohypacusis in childhood and adolescence is associated with increased gray matter volume in the medial frontal gyrus and superior temporal gyrus

Pseudohypacusis is a somatoform disorder characterized by hearing loss with discrepancies between pure-tone audiometry and auditory brainstem response (ABR), but the underlying neuronal mechanisms remain unclear. Using voxel-based morphometry (VBM) with magnetic resonance (MR) imaging for 14 unmedicated, right-handed patients and 35 healthy control subjects, we investigated whether functional hearing loss was associated with discernible changes of brain morphology. Group differences in gray matter volume (GMV) were assessed using high-resolution, T1-weighted, volumetric MR imaging datasets (3T Trio scanner; Siemens AG) and analyzed with covariant factors of age, sex, socioeconomic status (SES), and total GMV, which was increased by 27.9% in the left medial frontal gyrus (MFG) (Brodmann area 10) (p = .001, corrected cluster level) and by 14.4% in the right superior temporal gyrus (STG) and the adjacent middle temporal gyrus (MTG) (BA42 to 21) (p = .009, corrected cluster level) in patients with pseudohypacusis. The GMV in the right STG (BA42) and verbal intelligence quotient (IQ) were correlated significantly with the Wechsler Intelligence Scale for Children – Third Edition (WISC-III) (ß = ?.57, p < .0001) and level of SES (ß = ?.55, p < .0001). The present findings suggest that the development of the auditory association cortex involved in language processing is affected, causing insufficient pruning during brain development. We therefore assert that differences in the neuroanatomical substrate of pseudohypacusis subjects result from a developmental disorder in auditory processing.     

Aβ1-42合并IBO诱导阿尔茨海默病大鼠模型的建立和评价

目的建立一种新的复合式阿尔茨海默病（AD）大鼠模型，用于AD及其药物治疗的研究。方法SD雄性大鼠随机分为正常组、假手术组、模型组。在大鼠左侧海马区内注β-淀粉样蛋白1—42肽段（Aβ1-42）和鹅膏蕈氨酸（IB0）混合液造成AD模型，通过水迷宫试验比较各组差异。结果在定位航行中，模型组潜伏期明显比正常组和假手术组延长（P〈O．01）。结论Aβ1-42合并IBO诱导阿尔茨海默病大鼠模型在一定程度上较好的模拟AD的发病特点，可作为AD及其药物研究的一种新模型。     

Skin sensitizing properties of the ethanolamines mono‐, di‐, and triethanolamine. Data analysis of a multicentre surveillance network (IVDK*) and review of the literature

Numerous publications address the skin sensitizing potential of the short chain alkanolamines triethanolamine (TEA), diethanolamine (DEA), monoethanolamine (MEA), which are not skin sensitizing according to animal studies. Regarding TEA, we analysed patch test data of 85 098 patients who had been tested with TEA 2.5% petrolatum by Information Network of Departments of Dermatology (IVDK) to identify particular exposures possibly associated with an elevated risk of sensitization. Altogether, 323 patients (0.4%) tested positive. The profile of patch test reactions indicates a slightly irritant potential rather than a true allergic response in many cases. Although used widely, no exposure associated with an increased risk of TEA sensitization was identified. Therefore, the risk of sensitization to TEA seems to be very low. MEA and DEA were patch tested in a much more aimed fashion in 9602 and 8791 patients, respectively when prevalence of contact allergy was 3.8% and 1.8%. MEA is the prominent allergen in metalworkers with exposure to water‐based metalworking fluids (wbMWFs); DEA is probably used in cutting fluids less frequently nowadays. Chronic damage to the skin barrier resulting from wbMWF, the alkalinity of ethanolamines (increasing from TEA to MEA), and other cofactors may contribute to a notable sensitization risk.     

Small GTPases in lymphocyte biology

Almost a decade ago, the small GTPase Ras was shown to be activated in response to antigen receptor triggering in T cells. Since then, Ras has been further characterized as a central molecule for the regulation of signal transduction pathways in lymphocytes. However, over the last couple of years, its exclusive role in lymphocyte biology has been challenged by the emergence of its relatives of the Rho family. Today it is well established that Rho GTPases act as unique molecular switches at several critical checkpoints in lymphocyte development and function. Additionally, a new and critical concept in GTPase signaling has taken shape over the last couple of years in that small GTPases are able to regulate quite diverse cellular processes in the immune response by linking to multiple biochemical effector pathways.     

孕期氯氮平暴露对子代大鼠生长发育和脑MAPK44/42表达的影响

目的 建立孕期氯氮平暴露子代大鼠模型,观察孕期给药对子代造成的影响.方法 8周龄wistar雌鼠,分为对照组(n=17只)和用药组(n=25只),在大鼠孕6～15d,对照组腹腔注射生理盐水,用药组注射氯氮平针剂.观察子代大鼠体格发育、神经反射、神经行为以及脑MAPK表达.结果 氯氮平孕期暴露组导敛子代大鼠早期生长延迟,出生后第4天和第7天(F=12.56/7.51,P＜0.01)体质量增长低于对照组;神经发育指标显示悬崖回避反射在出生后第3天和第9天(F=4.969/4.348;P＜0.05)与对照组相比回避反应时间延长;空中翻正反射达标数目较对照组明显减少(F=7.959/6.457,P＜0.01/0.05);旷场行为试验未显示差异性;对出生后15d龄的子代大鼠海马及其前额叶皮质MAPK44/42表达检测显示:海马部位Pho-MAPK44/42表达显著低于对照组(F=18.729/23.824,P＜0.01),MAPK44/42表达2组差异无显著性;前额叶皮质Pho-MAPK44/42和MAPK44/42表达2组差异无显著性.结论 孕期氯氮平暴露可导致子代大鼠生长发育和脑发育异常.     

丹酚酸A对诱导Aβ42聚集的干预作用研究

摘要：目的 研究丹酚酸A对Aβ42聚集的干预作用。方法 利用ThT荧光实验法探究金属Zn2+对Aβ42聚集的影响,丹酚酸A对Aβ42聚集和解聚的影响,以及对金属Zn2+诱导Aβ42聚集的干预作用;在无水乙醇溶剂中,合成丹酚酸A-Zn(Ⅱ)配合物并对其结构进行表征,从而探究丹酚酸A对金属Zn2+诱导Aβ42聚集干预作用的机制及过程。结果 金属Zn2+促进Aβ42的聚集,丹酚酸A对Aβ42的聚集具有抑制作用,对Aβ42聚集体具有解聚作用,并且能明显抑制金属Zn2+诱导Aβ42的聚集;成功在体外合成丹酚酸A-Zn(Ⅱ)配合物,根据结构表征结果,推测其可能的结构式为1分子丹酚酸A与1分子金属Zn2+通过丹酚酸A的羧基和羧基邻位的苯环形成配合物,丹酚酸A能和Aβ42竞争性的络合金属Zn2+,从而抑制金属Zn2+诱导Aβ42的聚集和促进金属Zn2+诱导Aβ42聚集体的解聚。结论 丹酚酸A具有双靶点同时抑制作用,为探索丹参治疗AD的作用机制奠定基础。     

miR-146a靶向TRAF6继而抑制AR42J细胞的增殖及凋亡

目的探究miR-146a对胰腺腺泡细胞AR42J增殖及凋亡的影响。方法通过雨蛙素诱导AR42J细胞构建急性胰腺炎模型,酶联免疫吸附实验(ELISA)检测细胞上清液中淀粉酶、TNF-α、IL-6含量验证模型构建,qRT-PCR与Western blot分别检测各组中miR-146a和TRAF6表达量的改变。转染敲低AR42J细胞中miR-146a表达量,采用Edu检测细胞敲低后增殖改变,流式细胞术检测凋亡能力改变。结果与未处理组相比,雨蛙素组细胞miR-146a表达量显著降低(P<0.05),TRAF6表达量明显升高(P<0.05),并且敲低miR-146a后AR42J细胞增殖能力明显降低,凋亡能力明显升高。结论miR-146a可能通过抑制TRAF6表达从而降低AR42J细胞凋亡并促进细胞增殖能力。     

Aβ1-42抑制少突胶质前体细胞增殖与分化的实验研究

目的 探讨在离体细胞培养条件下,Aβ1-42对SD乳鼠少突胶质前体细胞(oligodendrocyte precursor cells,OPCs)增殖与分化的影响.方法 采用条件培养液原代培养获得高纯度SD乳鼠OPCs,分为正常组、加入无菌水的对照组、加入Aβ1-42的实验组,采用CCK-8检测存活细胞数量和增殖水平,Western blot检测细胞凋亡蛋白含量,免疫细胞化学染色观察细胞形态变化及分化情况.结果 与对照组相比,实验组OPCs存活率显著降低(P＜0.01),具体表现为:Aβ1-42作用OPCs 1 h后,细胞增殖明显受到抑制(P＜0.01);药物浓度1 moL/L作用于OPCs时,增殖也受到影响(P＜0.05),当Aβ1-42剂量增加至2.5 mol/L时,细胞增殖明显受到抑制(P＜0.01),而对照组与正常组无显著差异(P＞0.05).对凋亡蛋白Caspase-3的检测发现,它们在对照组与正常组的表达水平基本相当(P＞0.05),而在实验组明显升高(P＜0.01),且呈现时间和浓度依赖性,具体表现为:Aβ1-42作用OPCs 2 h后,Caspase-3表达水平明显上调(P＜0.01);药物浓度2.5 mol/L作用于OPCs时,蛋白表达水平有所升高(P＜0.05),当Aβ1-42剂量增加至5 mol/L时,Caspase-3表达水平明显上调(P＜0.01).对成熟少突胶质细胞标记物髓鞘碱性蛋白的免疫染色发现,与对照组相比,实验组的细胞体积明显变小,突起明显减少.结论 Aβ1-42可能通过促使细胞凋亡而抑制OPCs增殖,并抑制了OPCs向成熟少突胶质细胞分化,从而影响中枢神经系统的髓鞘形成.     

EPO对Aβ_（1-42）所致AD样大鼠空间记忆的影响及作用机制

目的探讨erythropoietin（EPO）对Aβ1-42所致AD样大鼠空间记忆的影响及作用机制。方法 48只雄性Wistar大鼠随机分成4组：生理盐水对照组、AD模型组、rHu-EPO治疗组与脑复康阳性对照组,每组12只。通过海马注射Aβ1-42的方法建立模型组,rHu-EPO治疗组与脑复康阳性对照组在建立模型的基础上,分别给予腹腔注射rhEPO（5000IU/kg,隔日一次）和脑复康（40 mg/kg,每日一次）。术后第八天开始对各组进行Morris水迷宫空间记忆能力测试,使用Western blot技术检测各组大鼠synapsin1蛋白水平。结果与生理盐水组、rHu-EPO治疗组及脑复康组相比,AD组水迷宫测试潜伏期延长,synapsin1表达降低,差异均有统计学意义（P〈0.05）。EPO治疗组与脑复康组相比,水迷宫测试结果与synapsin1蛋白表达差异无统计学意义（P〉0.05）。结论 EPO可以显著改善AD样大鼠的空间记忆能力,其机制可能与提高synapsin1蛋白表达有关。