脑源性神经营养因子在异常免疫应答相关神经系统变性疾病中的作用

神经系统变性疾病是一类由成熟神经元进行性变性、坏死所引起认知及行为异常的疾病,严重时会导致患者死亡,目前尚无有效的治疗手段。有研究表明,免疫应答异常普遍存在于中枢神经系统变性疾病过程中,并会导致蛋白质脑源性神经营养因子(BDNF)的减少,引起运动、认知及记忆等障碍。BDNF在神经系统变性疾病中免疫应答异常的作用可能涉及多种机制,虽然目前尚无定论,但BDNF相关的治疗手段,有可能从调节机体免疫能力的角度,为神经系统变性疾病的治疗提供新思路,有着重大的意义。因此,有关BDNF介导的免疫反应在神经系统变性疾病中作用的研究已成为近年来的热点。本文就此进行探讨,并对与BDNF相关的神经系统变性疾病的治疗手段进行综述。     

免疫应答异常与中枢神经系统退变性疾病

免疫功能异常参与了中枢神经系统退变性疾病的发生。中枢免疫功能异常主要为小胶质细胞异常激活。激活的小胶质细胞可形成活性中间代谢产物、一氧化氮、促炎因子等细胞毒性物质。发病率最高的两种中枢神经系统退变性疾病阿尔茨海默病（Alzheimer′s disease,AD)和帕鑫森病（Parkinson′s disease,PD)的发生都与免疫功能异常密切相关。由于免疫功能异常特别是小胶质细胞激活普遍存在于中枢神经系统退变性疾病过程中，调节小胶质细胞功能的药物可能会具有神经保护作用，延迟甚至阻止神经元变性。     

腰椎间盘退变的分子病理学变化及发病机制

背景：腰椎间盘退变是引起腰腿痛的常见原因,椎间盘退变的病理改变及发病机制至今仍未完全明确。 目的：介绍腰椎间盘退变的分子病理改变及其发病机制的研究进展。 方法：以“disc histology,disc degenerative disease,disc gene”等主题词检索PubMed数据库,检索时间为2005/2010年,筛选与腰椎间盘组织学变化和发病机制相关的文献,总结归纳腰椎间盘退变的研究进展和研究结果。 结果与结论：共检索到与腰椎间盘退变有关的文章118篇,共纳入30篇。结果表明腰椎间盘退变受多种因素影响,包括基因遗传因素、自然老化和积累性损伤等,基因的多形性是诱发退变的重要前置因素。椎间盘退变可通过免疫反应、机械性压迫或不稳定、血循环障碍和炎性递质等因素导致椎间盘退变性疾病。老化和病理性退变在影像和病理上难以区别,应根据椎间盘退变性疾病的具体情况采取合理的治疗方法,生物学治疗提供了新的治疗思路,但目前仍处在实验研究阶段。     

Tau蛋白异常磷酸化及其与AD病理机制的关系

<正>Alzheimer氏病(AD)是一种以进行性认识和记忆功能丧失为主要临床特征的神经系统退变性疾病。神经原纤维缠结(neurofibrillary tangles,NFT)和老年斑(Senile plaques,SP)在AD病人脑中大量出现是该病的两个主要病理特征,此外还有神经元和突触的丢失以及脑萎缩等现象。研究资料表明,NFT主要由高磷酸化tau蛋白聚集而成的双螺旋丝(Paired helical filaments,PHF)构成。本文就tau蛋白的结构和功能、tau蛋白的磷酸化及其调节、tau蛋白异常磷酸化与AD病理机制的关系等方面的研究进展作一综述。     

神经元和胶质细胞的相互作用与帕金森病

帕金森病是黑质多巴胺能神经元变性坏死而引起的神经系统退行性疾病。胶质细胞介导的免疫炎症反应是导致该疾病发生的主要因素之一。活化的小胶质细胞和星形胶质细胞释放的多种炎症因子不仅发挥着保护和(或)损伤神经元的作用,而且存在着复杂的相互联系和作用。不仅如此,神经元也可以反过来调控胶质细胞的活性。因此,在帕金森病的发病机理中,神经元和胶质细胞共同构成了一个复杂的神经系统网络。     

脑源性神经营养因子研究现状

近年来神经科学的研究表明,神经营养因子是选择性调节周围神经和中枢神经系统神经生长和存活的一类蛋白质。脑源性神经营养因子（brain derived neurotrophic factor,BDNF）是神经生长因子（nerve growth fac-tor,NGF)发现后约30年由德国神经生物学家Barde^[1]报告的另一神经营养因子,它对CNS多种类型神经元的生长、发育、分化、维持和损伤修复都具有重要作用,对神经系统疾病诸如早老性痴呆、帕金森氏病和肌萎缩侧索硬化等退变性疾病的治疗具有潜在应用前景。本文就脑源性神经营养因子的结构、功能及应用前景作一综述。     

蛋白聚集体形成研究进展

神经退行性疾病(neurodegenerative disorder)是由于神经元进行性变性死亡导致的以中枢神经系统损害为主的神经系统疾病.其中包括帕金森病、阿尔茨海默症、亨廷顿舞蹈病等.当错误折叠的蛋白超过分子伴侣的重新折叠和泛素-蛋白酶体系降解能力的时候,错误折叠的蛋白质可以通过被介导的动力蛋白马达逆向转运至微管组织中心周围形成蛋白聚集体.蛋白聚集体的形成被认为是细胞的一种防御反应,隔离有毒的错误折叠蛋白进而进行清除.蛋白聚集体通路的研究可为多种神经退变性疾病提供治疗靶点.     

帕金森病中关键致病因子α突触核蛋白的研究进展

帕金森病（PD）是中老年常见的慢性神经系统变性疾病，患病率和致残率均较高，是危害老年人健康的主要疾病之一。α突触核蛋白（α-Syn）的突变和异常聚集与PD的发生、发展密切相关，但尚未明确其致病机制。α-Syn是可溶性小分子蛋白，主要集中在脑部神经细胞中表达，     

腰椎间盘退变与COL9A2基因单核苷酸多态性的相关性

背景：有研究证实,腰椎间盘退变与基因有密切关系。 目的：探讨COL9A2基因单核苷酸多态性(rsl2722877、rs3737820和rs209914)与腰椎间盘退变性疾病的关系。 方法：腰椎间盘退变性疾病患者280例,年龄、性别匹配的268例非腰椎间盘退变性疾病患者作为正常对照组,均来自广西壮族。收集腰椎间盘退变性疾病患者、非腰椎间盘退变性疾病患者的血液样本,提取基因组DNA,设计针对COL9A2基因rsl2722877、rs3737820和rs209914位点的PCR引物、TaqMan探针,利用TaqMan探针技术对rsl2722877、rs3737820和rs209914位点进行PCR荧光分型。采用SPSS17.0软件进行等位基因频率及基因型频率分析。 结果与结论：rsl2722877、rs3737820和rs209914位点的各基因型与等位基因频率分布在病例组和对照组之间均差异有显著性意义(P < 0.05)。COL9A2基因单核苷酸多态性rsl2722877、rs3737820和rs209914与广西壮族人群腰椎间盘退变性疾病易感性密切相关。     

CONTRAST ANALYSIS ON BA AND CT IN 509 PATIENTS

目的：探讨脑电地形图与CT在常见神经系统疾病中的对比应用。方法：509例患者进行了脑电地形图和CT检查。结果：在509例患者中脑电地形图和脑CT显示了不同的改变。结论：脑电地形图和脑CT在常见神经系统疾病的诊断中，各具有其优点和不足。脑电地形图在常见神经系统疾病的临床应用中有重要价值。     

基于定量磁化率成像的脑发育及老化研究进展

铁元素和髓鞘的变化间接反映了大脑结构与功能的改变,并与多种神经退行性疾病相关。在脑发育及老化过程中,铁元素沉积和髓鞘形成与脱落的过程会引起脑组织磁化率数值的改变。定量磁化率成像（QuantitativeSusceptibility Mapping,QSM）是一种基于梯度回波（Gradient Recalled Echo,GRE）序列对磁化率进行定量的磁共振成像手段,可定量脑灰质中铁元素的沉积和脑白质中髓鞘的含量。有研究表明,可以基于QSM图像用指数和泊松函数拟合脑发育过程中铁元素与髓鞘的发展轨迹,得到与组织学等其他定量手段相似的结论。在此基础上,研究人员构建了基于QSM图像的全年龄脑图谱,为研究铁元素和髓鞘在脑老化及神经退行性疾病中的作用提供了基础。该文介绍了QSM成像原理及其在脑发育及老化定量研究中的最新进展。     

Circular RNAs: emerging players in brain aging and neurodegenerative diseases

Brain aging is closely related to neurodegenerative diseases. Circular RNAs (circRNAs) are a type of conserved RNAs with covalently closed continuous loops. Emerging evidence has shown that circRNAs are implicated in the biology of brain aging and the pathology of age-related neurodegenerative diseases. Here, we summarize current studies on circRNAs associated with brain aging and neurodegenerative diseases by discussing their expression features, pathophysiological roles, and mechanisms of action. We also discuss the potential challenges of circRNA-based therapy against brain aging and neurodegenerative diseases, as well as their potential as diagnostic biomarkers of neurodegenerative diseases. The review provides insights into current progress in the functions of circRNAs in the process of brain aging and neurodegenerative diseases. © 2022 The Pathological Society of Great Britain and Ireland.     

Are microRNAs true sensors of ageing and cellular senescence?

All living beings are programmed to death due to aging and age-related processes. Aging is a normal process of every living species. While all cells are inevitably progressing towards death, many disease processes accelerate the aging process, leading to senescence. Pathologies such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington’s disease, cardiovascular disease, cancer, and skin diseases have been associated with deregulated aging. Healthy aging can delay onset of all age-related diseases. Genetics and epigenetics are reported to play large roles in accelerating and/or delaying the onset of age-related diseases. Cellular mechanisms of aging and age-related diseases are not completely understood. However, recent molecular biology discoveries have revealed that microRNAs (miRNAs) are potential sensors of aging and cellular senescence. Due to miRNAs capability to bind to the 3′ untranslated region (UTR) of mRNA of specific genes, miRNAs can prevent the translation of specific genes. The purpose of our article is to highlight recent advancements in miRNAs and their involvement in cellular changes in aging and senescence. Our article discusses the current understanding of cellular senescence, its interplay with miRNAs regulation, and how they both contribute to disease processes.     

Molecular-genetic mechanisms of the pathogenesis of human diseases related to disorders of processes involved in the repair of DNA damage

One of the major systems providing cellular homeostasis is a system of DNA repair. Disorders of this system lead to the development of certain diseases, transformation of a normal cell into a malignant one, premature aging of a cell. The activity of reparative systems is related with an enzyme complex controlled by the corresponding genes. A number of hereditary diseases is described in which disturbances in the DNA reparative processes induced by physical or chemical mutagenes are found. Some diseases are also characterized by genome instability due to which there is a spontaneous increase in chromosome aberrations or sister chromatid exchanges. The impairment of the reparative DNA processes was first found in the author's laboratory in a number of hereditary diseases (Marfan's syndrome, homocystinuria) and diseases with hereditary prerisposition (schizophrenia). It is suggested that disorders of reparative DNA systems form the basis for molecular and genetic mechanisms of pathogenesis both in hereditary diseases, and the diseases with hereditary predisposition. Knowledge of the molecular level of cell organization in the pathologic state will ensure new methods of diagnosis and treatment.     

It was the best of times, it was the worst of times: a psychophysiologist's view of cognitive aging

This paper reviews research on age-related changes in working memory and attention control. This work is interpreted within a framework labeled "GOLDEN aging" (growing of lifelong differences explains normal aging), which is based on the idea that normal aging (as opposed to pathological aging) represents maturational processes causing progressive shifts in the distributions of mental abilities over the lifespan. As such, brain phenomena observed in normal aging are already apparent, under appropriate conditions, in younger adults. Among the phenomena that can be interpreted according to the GOLDEN aging framework are reductions in working memory capacity, impairments of inhibitory processes, increases in frontal lobe activation, and lack of suppression of responses as a function of repetition.     

The aging brain: less neurons could be better

Molecular and cellular markers of age-related alterations in the brain vary significantly between different brain regions and between different types of neurons. In contrast to what had been thought for years, it has recently become clear that only specific types of neurons show an age-related loss of cells. Based on previous work we hypothesize that there is an interrelationship between two important processes in the aging brain: some types of neurons in the aging brain show an accumulation of unrepaired nuclear (n) nDNA damage since no cells are lost during aging. In contrast, other types of neurons show no accumulation of unrepaired nDNA damage since the cells with the greatest decline in nDNA repair capacity and the highest amount of nDNA damage are lost during aging. Most interestingly, the former types of neurons seem to correlate strongly with those types of neurons afflicted in age-related cognitive decline and in the selective neuronal vulnerability in Alzheimer's disease. Therefore, modulation of the nDNA damage response by stimulation of nDNA repair processes, or by elimination of neurons with a high amount of unrepaired nDNA damage in the aging brain, may lead to a functional improvement in networks of these types of neurons and to a better functioning of the aging brain in general. Ultimately, the implication of this strategy may lead to the prevention of AD.     

Neuronal and microglial cathepsins in aging and age-related diseases

It has been long believed that cathepsins compensate for each other because of their overlapping substrate specificities. However, there is increasing evidence that disturbance of the normal balance of their enzymatic activities is the first insult in brain aging and age-related diseases. The imbalance of cathepsins may further cause age-related neuropathological changes such as accumulation of autophagic vacuoles and the formation of ceroid-lipofuscin leading to neuronal dysfunction and damage. Leakage of cathepsins due to the fragility of lysosomal membranes during aging also contributes to neurodegeneration. Furthermore, the deficiency of cathepsin D has been recently revealed to provoke a novel type of lysosomal storage disease associated with massive neurodegeneration. In these animals, microglia are activated to initiate inflammatory and cytotoxic responses by binding and phagocytosis of storage neurons. Activated microglia also release some members of cathepsins to induce neuronal death by degrading extracellular matrix proteins. Thus the microglial activation possibly through sensing neuronal storage may also be an important causative factor for neurodegeneration in lysosomal storage diseases and age-related diseases such as Alzheimer's disease. This review describes the pathological roles of neuronal and microglial cathepsins in brain aging and age-related diseases.     

Expression of Ambra1 in mouse brain during physiological and Alzheimer type aging

Autophagy is a major protein degradation pathway, essential for stress-induced and constitutive protein turnover. In nervous tissue, autophagy is constitutively active and crucial to neuronal survival. The efficiency of the autophagic pathway reportedly undergoes age-related decline, and autophagy defects are observed in neurodegenerative diseases. Since Ambra1 plays a fundamental role in regulating the autophagic process in developing nervous tissue, we investigated the expression of this protein in mature mouse brain and during physiological and Alzheimer type aging. The present study accomplished the first complete map of Ambra1 protein distribution in the various brain areas, and highlights differential expression in neuronal/glial cell populations. Differences in Ambra1 content are possibly related to specific neuronal features and properties, particularly concerning susceptibility to neurodegeneration. Furthermore, the analysis of Ambra1 expression in physiological and pathological brain aging supports important, though conflicting, functions of autophagy in neurodegenerative processes. Thus, novel therapeutic approaches, based on autophagy modulation, should also take into account the age-dependent roles of this mechanism in establishing, promoting, or counteracting neurodegeneration.     

脑内铁积聚与神经退行性疾病

过渡金属(铜、锌、铁等)在脑内异常沉积及其代谢紊乱是多种神经退行性疾病的重要病因。普通老年人和神经退行性疾病患者的脑内均有铁沉积增多的趋势,但调节铁代谢的转铁蛋白在脑组织中并没有相应增多,从而增加产生氧化应激的风险。然而在阿尔茨海默病(Alzheimer′s,AD)和帕金森氏病(Parkinson′s,PD)患者脑内铁含量异常增多的原因尚不明确。因此,研究脑内铁代谢在神经退行性疾病的起病、进展等各阶段中的作用,已成为神经生物学领域的一个重要课题。