晚期糖基化终末产物受体及其配体在阿尔茨海默病发病机制中的作用及其临床意义

晚期糖基化终末产物(AGEs)受体(RAGE)是一种免疫球蛋白超家族的多配体受体,其配体包括AGEs,S100/Ca2+、β淀粉样蛋白和两性蛋白B等.位于细胞膜表面的RAGE与配体结合后可启动若干信号通路,导致持续的细胞功能紊乱,参与了多种疾病的发生、发展.近年来,越来越多研究发现RAGE及其配体对阿尔茨海默病的主要病理改变——Aβ沉积存在一定影响.可通过拮抗RAGE与其配体结合来阻断其在AD发生发展中的作用.     

福建医科大学附属第一医院神经科参与完成的论文在Nature Medicine上发表

多发性硬化 (MS)是神经科常见的自身免疫性疾病之一。福建医科大学附属第一医院神经科吴志英副教授与美国哥伦比亚大学合作 ,通过体内和体外研究 ,在分子水平及细胞水平证实 :晚期糖基化终末化产物受体 (RAGE)在MS及实验性变应性脑炎 (EAE)小鼠模型表达量增高 ;重组的可溶性RAGE蛋白及其抗体可阻断其症状、降低RAGE的表达、抑制免疫 /炎症细胞浸润中枢神经系统的 ;CD+ 4 DN RAGE转基因鼠可对抗髓磷脂碱性蛋白 (MBP)的诱导作用。这些结果表明RAGE与其配体S1 0 0结合 ,参与调控CD+ 4T细胞浸润中枢神经系统的作用 ,抑制RAGE…     

配体-RAGE、sRAGE与动脉粥样硬化的关系

晚期糖基化终产物受体(receptor for advanced glycationend products,RAGE)作为一种细胞信号转导受体,参与动脉粥样硬化(AS)的形成。它与多种配体结合激活p21、ras、p38丝裂原活化蛋白激酶(MAPK)、核转录因子(NF-κB)等主要的细胞信号转导途径,参与炎症反应等生理和病理过程[1],与AS的损伤反应学说有关。而血浆和组织中亦存在一种特殊的RAGE亚型,即可溶性晚期糖基化终产物受体(sRAGE),可与RAGE竞争结合其配体,抑制RAGE诱导的     

朊蛋白(PrPc)生理功能的研究进展

朊蛋白是主要分布在神经系统的一种糖蛋白,对其生理功能的研究已逐渐成为Prion病研究领域内的另一个热点.朊蛋白可以作为受体与配体结合,传递胞内或胞外信号,它还可能具有抗氧化活性和抗细胞凋亡的特性.     

PPARγ激动剂与小胶质细胞和中枢神经系统炎症变性疾病的关系

过氧化物酶体增殖物活化受体γ(PPARγ)是一种核转录因子,属由配体激活的Ⅱ型核受体超家族的成员。PPARγ除参与脂质代谢、胰岛素抵抗、脂肪细胞分化、动脉粥样硬化和肿瘤生成外,还参与炎症反应及免疫调节。PPARγ激动剂能通过PPARγ依赖或非依赖机制抑制活化的小胶质细胞、保护神经元、促进活化的小胶质细胞凋亡从而控制中枢神经系统(CNS)炎症变性疾病如阿茨海默病(AD)、帕金森病(PD)和多发性硬化(MS)。提示PPARγ激动剂有可能成为一类很有治疗CNS炎症性及退行性变性疾病前景的药物。     

Notch信号在神经系统发育中的多效性

Notch受体介导的信号通路在神经系统发育中发挥着至关重要的作用.Notch是高度保守的信号通路,它通过受体配体的相互作用以及之后的一系列核内分子事件影响相邻细胞的分化命运.以往大量研究结果揭示Notch信号的激活维持了神经干及前体细胞特性,抑制神经元产生并促进胶质细胞生成.最近的研究进展显示Notch信号新的组成分子、新的作用模式、对成熟神经元形态与功能以及对少突胶质细胞生成髓鞘过程的调控作用.综上所述,Notch信号不仅在神经发育中扮演重要角色,还有可能在中枢神经损伤、多发性硬化等疾病的治疗中发挥自己独有的作用,彻底阐明其作用机制在未来对这些疾病新的治疗方法的建立意义重大.本文旨在综述Notch信号在神经系统发育中多方面的功能,并讨论该研究领域的最新进展.     

小胶质细胞显像原理及其在帕金森病和阿尔茨海默病的应用

神经炎症伴随小胶质细胞的激活是一系列神经系统疾病的共同特征。在激活的小胶质细胞中,转位蛋白(TTSPO)表达上调。利用TSPO放射性配体进行正电子发射断层扫描显像,可以观察和研究脑内神经炎性反应的进展及严重程度。文中综述小胶质细胞显像的原理及在神经退行性疾病,如在帕金森病和阿尔茨海默病的应用。     

过氧化物酶体增殖物激活受体γ在中枢神经系统疾病中作用的研究进展

过氧化物酶体增殖物激活受体Υ(PPARΥ)是一种配体激活的核转录医子.它参与调节脂质代谢、脂肪生成、胰岛素敏感、炎症反应、细胞生长和分化等重要生化反应及生物调节过程.本文先对PPARΥ及其配体做一简介,然后就其在脑缺血及缺血再灌注损伤、创伤性脑外伤及脊髓损伤、癫痫、运动障碍性疾病、神经变性性疾病和脱髓鞘疾病中的抗炎、抗氧化作用及其机制进行综述.     

糖基化终末产物对人神经母细胞瘤细胞APP表达及Aβ生成的影响

目的通过研究糖基化终末产物（AGEs-BSA）以及阻断其与特异性受体RAGE的结合对培养的人神经母细胞瘤细胞（SH-SY5Y）淀粉样前体蛋白（amyloid precursor protein,APP）的表达以及β淀粉样蛋白（β-amyloid,Aβ）生成的影响。方法以培养的SH-SY5Y细胞为模型,将细胞随机分为4组,空白对照组、BSA组、AGEs-BSA组、AGEs-BSA＋抗RAGE中和抗体组。用MTT法观察细胞形态以及确定AGEs-BSA的最佳干预时间及浓度。用免疫细胞化学方法及免疫印迹方法来检测各组细胞内APP、RAGE表达和Aβ生成情况。结果不同蛋白浓度的BSA处理细胞24、48、72h,与空白对照组比较细胞MTT代谢率,APP、RAGE及Aβ的表达水平没有明显差异,（P〉0.05）;不同蛋白浓度的AGEs-BSA（〉50μg/ml）处理细胞与BSA组比较,细胞MTT代谢率明显降低,并随蛋白浓度升高差异越明显,APP、RAGE、Aβ的表达水平较BSA组明显增加（P〈0.05）,预先用抗RAGE中和抗体（1∶100）1h后再加入AGEs-BSA,APP、Aβ的表达水平较AGEs-BSA组明显减少（P〈0.05）,但仍高于BSA组（P〈0.05）。结论糖基化终末产物能够促使SH-SY5Y细胞中APP、RAGE、Aβ的表达和生成增加。通过阻断其与特异性受体RAGE的结合可以部分减少APP、Aβ的表达和生成。     

PPARγ的神经保护作用研究进展

过氧化物酶体增殖物激活受体（peroxisome proliferator—activated receptors,PPARs）是配体活化的核转录因子,属Ⅱ型核受体超家族成员之一,有α、β、γ3种亚型。PPARγ在1990年由Isseman等首次发现存在于脂肪细胞的分化调控通路中,故又称为脂激活转录因子。该受体被其配体激活后可以和特异的DNA反应元件结合,调控多种基因的转录和表达,参与体内多种生理和病理过程,如血糖调节、脂肪代谢。     

Development of the projection from the nucleus of the brachium of the inferior colliculus to the superior colliculus in the ferret

Neurons in the deeper layers of the superior colliculus (SC) have spatially tuned receptive fields that are arranged to form a map of auditory space. The spatial tuning of these neurons emerges gradually in an experience-dependent manner after the onset of hearing, but the relative contributions of peripheral and central factors in this process of maturation are unknown. We have studied the postnatal development of the projection to the ferret SC from the nucleus of the brachium of the inferior colliculus (nBIC), its main source of auditory input, to determine whether the emergence of auditory map topography can be attributed to anatomical rewiring of this projection. The pattern of retrograde labeling produced by injections of fluorescent microspheres in the SC on postnatal day (P) 0 and just after the age of hearing onset (P29), showed that the nBIC-SC projection is topographically organized in the rostrocaudal axis, along which sound azimuth is represented, from birth. Injections of biotinylated dextran amine-fluorescein into the nBIC at different ages (P30, 60, and 90) labeled axons with numerous terminals and en passant boutons throughout the deeper layers of the SC. This labeling covered the entire mediolateral extent of the SC, but, in keeping with the pattern of retrograde labeling following microsphere injections in the SC, was more restricted rostrocaudally. No systematic changes were observed with age. The stability of the nBIC-SC projection over this period suggests that developmental changes in auditory spatial tuning involve other processes, rather than a gross refinement of the projection from the nBIC.     

Mechanisms of the suppression of the nociceptive reflex of the opening of the mouth during stimulation of the structures of the limbic brain

The comparative effectiveness of the inhibitory influence of tetanic stimulation of hypothalamus, amygdala and limbic cortex on EMG-response of m. digastricus evoked by electrical stimulation of tooth pulp nociceptive afferents was studied in cats anesthetized with a mixture of chloralose and nembutal. It was found that inhibition of the EMG-component of the jaw-opening reflex is most pronounced in case of stimulation of medial and lateral region of the hypothalamus, the inhibitory effect of central and medial nuclei of the amygdala is less pronounced and the effect of the limbic cortex is the weakest. It was shown that the mechanism of the antinociceptive effect of tetanic stimulation of the hypothalamus is not related to the concomitant increase of the blood pressure. After stabilization of the blood pressure the suppressive effect of the hypothalamus remains without changes, that points out to a direct, primary, not baro-afferent mechanism of the inhibition of the activity of nociceptive neurons of the trigeminal sensory nuclei. Noradrenaline, injected intravenously, induced a large increase of the blood pressure accompanied by a pronounced inhibition of the pain reflex. Angiotensin causes the same degree of blood pressure elevation without changes in the amplitude of the EMG-response of the pain reflex. Hypothalamic and noradrenergic mechanisms for control of pain sensitivity are discussed.     

The organization of the connections between the cortex and the claustrum in the monkey

The distribution of labelled cells and of extracellular granules in the claustrum has been studied after injections of horseradish peroxidase in several areas of the neocortex. The frontal and parietal lobes are related to the anterior and posterior halves respectively of the claustrum, and the occipital and temporal cortex to the posterior and inferior margins. Parts of the claustrum related to areas of the cortex in the frontal lobe overlap considerably in the antero-posterior dimension with parts related to widely separated but interconnected areas of the parieto-temporal cortex. Areas of cortex within one lobe which are interconnected are related to parts of the claustrum which overlap in the dorsoventral dimension.     

Investigating the construct validity of the SPAI-C: comparing the sensitivity and specificity of the SPAI-C and the SAS-A

Investigates the construct validity of the Social Phobia and Anxiety Inventory for Children (SPAI-C) by comparing its sensitivity and specificity with another self-report measure of social anxiety, the Social Anxiety Scale for Adolescents (SAS-A). Participants were 252 adolescents (124 males and 128 females) 13-17 years old. Adolescents completed the SPAI-C and the SAS-A and were interviewed using the Anxiety Disorders Interview Schedule for DSM-IV: Child Version (ADIS-IV:C). Parents were also interviewed and composite diagnoses were formed. Youth were classified as socially phobic or non-anxious based on these composite diagnoses. By comparing clinical cutoff scores with diagnostic group classification, the sensitivity and the specificity of the SPAI-C and SAS-A were compared. Results indicated that the SPAI-C was a more sensitive measure than the SAS-A (61.5% vs. 43.6%) providing evidence of the scale's construct validity. The two measures were similar with regard to specificity (82.7% for both). Implications of these results for assessment and research are discussed.