阿尔茨海默病中的氧化应激及抗氧化治疗

氧化损伤是阿尔茨海默病(AD)的一个重要特征,故"氧化应激假说"提出AD中氧化应激产生较早,可在轻度认知功能障碍及分子水平改变出现即β淀粉样蛋白沉积及神经纤维缠结的形成之前,导致细胞和组织损伤,促进疾病进展.氧化应激中增高的氧化损伤标记水平、抗氧化系统中特定活性的改变、线粒体功能失调及与tau蛋白磷酸化及聚集,β淀粉样蛋白斑块之间联系紧密.本综述探讨AD中的氧化应激假说,抗氧化治疗AD中的可行性及展望.     

糖脂代谢参与糖尿病脑损伤的研究进展

糖尿病脑损伤是糖尿病(diabetes mellitus,DM)的主要并发症之一,表现为海马区神经细胞损伤、β-淀粉样蛋白沉积、Tau蛋白异常磷酸化与神经纤维缠结的形成、突触可塑性下降、脑萎缩和痴呆等类似于阿尔茨海默病(alzheimer's disease,AD)样改变。糖脂代谢异常与DM脑损伤发生有密切关系。胰岛素抵抗、线粒体功能障碍、氧化应激等在糖脂代谢异常中起重要作用。通过研究糖脂代谢在DM脑损伤的作用机制,以期从代谢的角度,寻找延缓DM脑损伤、防治AD的新方法。     

OA诱导大鼠基底核Ach降低及τ蛋白过度磷酸化

研究了磷酸酯酶(proteinphosphatase,PP)对胆碱能神经元功能的影响,将PP抑制剂岗田酸(okadaic acid,OA)注入大鼠双侧Meynert基底核,并经免疫印迹检测r(tau)蛋白磷酸化程度、经微渗透结合HL,PC检测Ach、经Morris水迷宫检测大鼠的空间记忆能力,结果发现,Meynert基底核注射OA后,Ach水平降低,τ蛋白在Sei-198／Sei-199／Set-202,Ser-396／Ser-404位点发生过度磷酸化,并伴有大鼠空间记忆障碍,本研究结果提示PP活性降低可能参与了神经元纤维缠结形成、胆碱能神经元功能及认知功能障碍,在AD发病机制中起重要作用。     

阿尔茨海默氏症分子病理学及治疗方法的研究进展

阿尔茨海默氏症是一种神经退行性疾病，是老年人的常见病、多发病，严重危害老年人的身心健康．近10年来，人们对其病因、病理进行了广泛的研究，认为自由基氧化胁迫和蛋白质的错误折叠是最基本的分子病理学机制，Aβ淀粉样沉积和tau蛋白引起的神经元纤维缠结是后的具体表现．综述了近10年对阿尔茨海默氏症的分子病理学研究进展及目前对其进行治疗的中西医方法．     

阿尔茨海默病相关药物靶点和临床治疗进展

阿尔兹海默病(Alzheimer’s disease, AD),俗称老年痴呆症,是一类典型的神经退行性疾病,是导致认知障碍的主要原因.目前阿尔兹海默病的发病机制仍不清楚.AD的典型病理特征是患者大脑中出现β-淀粉样蛋白(amyloid-β, Aβ)聚集形成的老年斑、tau蛋白过度磷酸化形成的神经元纤维缠结、神经元及突触的功能失调、大脑中的长期慢性炎症,最终发生退行性病变等.因此人们针对其病理特征提出了四大阿尔兹海默症发病机制假说,即Aβ假说、tau蛋白假说、神经递质失调假说以及慢性炎症假说.基于这些假说,科研工作者开发了大量基于不同病理机制的药物.本文将重点展示近四年来备受瞩目的阿尔兹海默病治疗药物的研究进展和临床试验结果,并总结探讨基于不同病理机制的药物研发的最新进展.综合阿尔兹海默病药物的研发情况可以使科研工作者更好地了解药物研发的困难,从而揭示药物研发的正确方向,同时也可以为阿尔兹海默病发病机制的探究提供有价值的线索.     

微管剪切蛋白调控果蝇节律神经元的形态发育

Spastin、Katanin60和Fidgetin是3种重要的微管剪切蛋白,它们的突变会导致神经退行性疾病。然而,这些微管剪切蛋白如何调节神经元的形态和功能尚不明确。果蝇的昼夜节律行为主要受位于大脑腹外侧的4对神经元LNv的控制。LNv神经元具有简单的形态,并且其轴突末梢会随着昼夜节律而伸缩。本研究利用LNv神经元作为模型,探讨不同微管剪切蛋白在神经元形态发育中的功能差异。我们发现,在LNv神经元中组成性表达Spastin会导致轴突和树突的发育异常,并且抑制神经肽PDF的转运;在成虫时期特异性表达Spastin会引起神经纤维的退化。而在LNv神经元中过量表达Katanin60或Fidgetin则不会影响LNv神经元的形态和神经肽PDF的转运。我们的结果揭示了不同微管剪切蛋白在不同神经元中具有不同的功能特性。     

阿尔采末病发病机制研究进展新视点

阿尔采末病的发病机制一直是神经科学领域未解的难题.近年来最新研究发现tao蛋白过度磷酸化导致神经纤维缠结、轴浆运输障碍、同型半胱氨酸的非血管作用、免疫学机制等导致神经元损伤和凋亡,最终引起阿尔采末发病.     

阿尔采末病发病机制研究进展新视点

阿尔采末病的发病机制一直是神经科学领域未解的难题。近年来最新研究发现tao蛋白过度磷酸化导致神经纤维缠结、轴浆运输障碍、同型半胱氨酸的非血管作用、免疫学机制等导致神经元损伤和凋亡,最终引起阿尔采末发病。     

运动对阿尔茨海默病的防治及其机制分析

阿尔茨海默病,又叫老年性痴呆,是一种神经系统退行性疾病。该病的发病机制目前认可的学说有Aβ毒性学说、tau蛋白异常磷酸化学说、胆碱能损伤学说、自由基损伤学说、兴奋性氨基酸毒性学说、钙平衡失调学说等。目前临床上尚无根治该病方法,预防就是最好的治疗。适宜的体育运动可以减少Aβ在脑内的过度沉积、抑制tau蛋白的异常磷酸化、帮助维持胆碱能系统正常运作、增强机体清除自由基的能力、防止兴奋性氨基酸毒性和修复细胞内钙超载。因此,体育运动不仅能够预防阿尔茨海默病的发生,还能够有效地干预阿尔茨海默病的发病进程。本文就运动对阿尔茨海默病防治机制的研究进展作一综述。     

以Aβ为靶的老年性痴呆的治疗策略

老年性痴呆（Alzheimerdisease，AD）是以进行性认知障碍和记忆能力损害为主的中枢神经系统退变性疾病。其主要病理变化包括老年斑（senileplaque，SP）、神经纤维缠结（neurofibrillarytungle，NFT）和选择性神经元及突触的丢失。由于AD病因和病理机制尚不清楚，其治疗亦缺乏理想的方法。传统的治疗方法主要有：脑细胞活化剂、心理治疗、拟胆碱药物治疗等等。前者似乎疗效不大，后者因其义才神经有一定的毒性，限制了临床应用。现行的AD治疗研究策略主要包括两个方面：（1）开发新的低毒性的拟胆碱药物；（2）神经营养物质的应用，包…     

The Effect of cdk-5 Overexpression and Overactivation on Tau Hyperphosphorylation in Cultured N2a Cells

Neurofibrillary tangles (NFTs) are one of the neuropathological hallmarks of Alzheimer‘s disease (AD) and abnormally hyperphosphorylated tau is the major protein of NFTs. It was reported that cyclin-dependent kinase5 (Cdk-5) could phosphorylate tau at most AD-related epitopes in vivo. In this study, we investigated the effect of cdk-5 overexpression on tau hyperphosphorylation in neuroblastoma N2a cells. We demonstrated that overexpression of cdk-5 whieh rcsul-ted in a 3.5-fold Cdk-5 activation in the transfected cells induced a dramatic increase in phosphorylation of tau at several phosphorylation sites. Overexpression of cdk-5 led to a reduced staining with antibody Tau-1 and an enhanced staining with antibody PHF-1, suggesting hyperphosphorylation of tau at Ser199/202 and Ser396/404 sites. It implies that in vitro overexpression of cdk-5 leads to Cdk-5 overactivation and tau hyperphosphorylation may be the underline mechanism.     

A dimorphic pheromone circuit in Drosophila from sensory input to descending output

Drosophila show innate olfactory-driven behaviours that are observed in naive animals without previous learning or experience, suggesting that the neural circuits that mediate these behaviours are genetically programmed. Despite the numerical simplicity of the fly nervous system, features of the anatomical organization of the fly brain often confound the delineation of these circuits. Here we identify a neural circuit responsive to cVA, a pheromone that elicits sexually dimorphic behaviours. We have combined neural tracing using an improved photoactivatable green fluorescent protein (PA-GFP) with electrophysiology, optical imaging and laser-mediated microlesioning to map this circuit from the activation of sensory neurons in the antennae to the excitation of descending neurons in the ventral nerve cord. This circuit is concise and minimally comprises four neurons, connected by three synapses. Three of these neurons are overtly dimorphic and identify a male-specific neuropil that integrates inputs from multiple sensory systems and sends outputs to the ventral nerve cord. This neural pathway suggests a means by which a single pheromone can elicit different behaviours in the two sexes.     

Deconstruction of a neural circuit for hunger

Hunger is a complex behavioural state that elicits intense food seeking and consumption. These behaviours are rapidly recapitulated by activation of starvation-sensitive AGRP neurons, which present an entry point for reverse-engineering neural circuits for hunger. Here we mapped synaptic interactions of AGRP neurons with multiple cell populations in mice and probed the contribution of these distinct circuits to feeding behaviour using optogenetic and pharmacogenetic techniques. An inhibitory circuit with paraventricular hypothalamus (PVH) neurons substantially accounted for acute AGRP neuron-evoked eating, whereas two other prominent circuits were insufficient. Within the PVH, we found that AGRP neurons target and inhibit oxytocin neurons, a small population that is selectively lost in Prader-Willi syndrome, a condition involving insatiable hunger. By developing strategies for evaluating molecularly defined circuits, we show that AGRP neuron suppression of oxytocin neurons is critical for evoked feeding. These experiments reveal a new neural circuit that regulates hunger state and pathways associated with overeating disorders.     

依达拉奉对脑缺血再灌注后Aβ及其前体表达干预

为探讨缺血再灌注对大鼠海马区神经元细胞的损伤机制及依达拉奉的干预作用,利用大脑中动脉线栓法制备大鼠脑缺血再灌模型,缺血2 h后再灌注22 h(术后24 h),按照Zea Longa 5级评分法,对大鼠进行神经行为学评分;通过苏木精-伊红染色法(HE)染色大鼠脑组织,观察其病理形态学的改变;通过免疫组织化学,图像分析及Western Blot的方法检测大鼠海马区β淀粉样蛋白(Aβ)及其前体(APP)的表达。结果显示,模型组大鼠表现出明显的神经功能缺损症状,与之相比,6和10 mg/kg的依达拉奉可不同程度改善损伤模型大鼠的神经缺损症状,尤其是10 mg/kg依达拉奉组的大鼠症状改善更为明显(P0.01);HE染色结果显示,模型组大鼠海马区神经元细胞脱失明显,而治疗组可减轻这种形态学改变;免疫组织化学及Western Blot分析结果提示,在模型组中Aβ、APP表达明显高于假手术组(P0.01),而在不同质量分数依达拉奉组中,Aβ、APP含量均减弱(P0.05)。由此得出,缺血再灌注可能通过上调淀粉样蛋白Aβ及其前体APP而引起神经元细胞损伤,而依达拉奉可能通过对它们的抑制起到保护神经元细胞的作用。     

阿尔茨海默病患者经颅磁刺激治疗的meta分析

 目前经颅磁刺激（repetitive transcranial magnetic stimulation）对阿尔茨海默病（Alzheimer's disease）的疗效具有争议性。检索2015年12月以前Embase、medline、Cochrane Library、Ovid、Pubmed、Web of science、中国知网、万方医学网数据库,按照既定的纳入标准和排除标准查找rTMS治疗AD的临床随机对照试验。使用RevMan5.3软件,应用标准误均数差（stan-dardised mean difference）,95%可信区间（confidence interval）分析。共纳入5个随机对照试验进行meta分析,共223例患者,其中rTMS组137例,对照组86例,MMSE结果显示rTMS组疗效线显著优于对照组,（SMD=1.05,95%CI:0.21、1.88,p=0.01,n=141）,亚组分析显示高频组（>1 Hz）（p=0.02）疗效优于低频组（≤1 Hz）（p=0.27）;ADAS-cog结果显示rTMS治疗显著优于对照组,（SMD=-0.71,95%CI:-1.04、-0.39,p<0.0001,n=168）,高频组（>1 Hz）（p<0.001）比低频组（≤1 Hz）（p=0.05）疗效更佳。分析结果显示rTMS对AD认知功能有显著改善效果,且高频治疗效果优于低频治疗,然而仅纳入5个研究,后期需要增大随机对照试验样本量验证上述结论。     

A role for adult TLX-positive neural stem cells in learning and behaviour

Neurogenesis persists in the adult brain and can be regulated by a plethora of external stimuli, such as learning, memory, exercise, environment and stress. Although newly generated neurons are able to migrate and preferentially incorporate into the neural network, how these cells are molecularly regulated and whether they are required for any normal brain function are unresolved questions. The adult neural stem cell pool is composed of orphan nuclear receptor TLX-positive cells. Here, using genetic approaches in mice, we demonstrate that TLX (also called NR2E1) regulates adult neural stem cell proliferation in a cell-autonomous manner by controlling a defined genetic network implicated in cell proliferation and growth. Consequently, specific removal of TLX from the adult mouse brain through inducible recombination results in a significant reduction of stem cell proliferation and a marked decrement in spatial learning. In contrast, the resulting suppression of adult neurogenesis does not affect contextual fear conditioning, locomotion or diurnal rhythmic activities, indicating a more selective contribution of newly generated neurons to specific cognitive functions.     

Application of EEG multipole model in the diagnosis of Alzheimer''''s disease

In order to find the electroencephalogram （EEG） characteristic parameters typical of Alzheimer＇s disease （AD） and explore an effective diagnostic method, a new mobile current multipole model was proposed to simulate the AD patient＇s cortical dipole source activities. The indicators of goodness of fit （GOF） and DtononD （DD） were calculated from EEG samples to evaluate the performance of this model. Relevant results showed that this multipole model with higher GOFvalues and larger DD change well fitted the pathological electrical activities of cortical neurons aroused by AD＇s extended sulcus and gyrus in the cerebral cortex. Meanwhile, the products of DD mean ＆ standard variance were found in a clear linear correlation with the diagnostic data of mini-mental state examination （MMSE） used in AD clinics. Furthermore, by tracing this multipole model＇s indicators in typical patients and contrasting with the functional magnetic resonance image （fMRI） as AD progressed, we suggested that the DD index may be suitable for monitoring the AD developments as a new diagnostic parameter.     

Development of an invasive brain machine interface with a monkey model

Brain-machine interfaces (BMIs) translate neural activities of the brain into specific instructions that can be carried out by external devices. BMIs have the potential to restore or augment motor functions of paralyzed patients suffering from spinal cord damage. The neural activities have been used to predict the 2D or 3D movement trajectory of monkey’s arm or hand in many studies. However, there are few studies on decoding the wrist movement from neural activities in center-out paradigm. The present study developed an invasive BMI system with a monkey model using a 10×10-microelectrode array in the primary motor cortex. The monkey was trained to perform a two-dimensional forelimb wrist movement paradigm where neural activities and movement signals were simultaneous recorded. Results showed that neuronal firing rates highly correlated with forelimb wrist movement; > 70% (105/149) neurons exhibited specific firing changes during movement and > 36% (54/149) neurons were used to discriminate directional pairs. The neuronal firing rates were also used to predict the wrist moving directions and continuous trajectories of the forelimb wrist. The four directions could be classified with 96% accuracy using a support vector machine, and the correlation coefficients of trajectory prediction using a general regression neural network were above 0.8 for both horizontal and vertical directions. Results showed that this BMI system could predict monkey wrist movements in high accuracy through the use of neuronal firing information.     

En passant neurotrophic action of an intermediate axonal target in the developing mammalian CNS.

During development, neurons extend axons to their targets, then become dependent for their survival on trophic substances secreted by their target cells. Competition for limiting amounts of these substances is thought to account for much of the extensive naturally-occurring cell death that is seen throughout the nervous system. Here we show that spinal commissural neurons, a group of long projection neurons in the central nervous system (CNS), are also dependent for their survival on trophic support from one of their intermediate targets, the floor plate of the spinal cord. This dependence occurs during a several-day-long period when their axons extend along the floor plate, following which they develop additional trophic requirements. A dependence of neurons on trophic support derived en passant from their intermediate axonal targets provides a mechanism for rapidly eliminating misprojecting neurons, which may help to prevent the formation of aberrant neuronal circuits during the development of the nervous system.