Decreased sAβPPβ, Aβ38, and Aβ40 cerebrospinal fluid levels in frontotemporal dementia

To improve the etiological diagnosis of neurodegenerative dementias like Alzheimer's disease (AD) or frontotemporal dementia (FTD), we evaluated the value of individual and combined measurements of the following relevant cerebrospinal fluid (CSF) biomarkers: Tau, 181p-Tau, Aβ38, Aβ40, Aβ42, sAβPPα, and sAβPPβ. This study conducted in two centers included patients with FTD (n = 34), AD (n = 52), as well as a control group of persons without dementia (CTRL, n = 42). Identical clinical criteria and pre-analytical conditions were used while CSF biomarkers were measured using commercial single and multiplex quantitative immunoassays. Thorough statistical analyses, including ROC curves, logistic regressions, and decision trees, were performed. We validated in AD the specific increase of p-Tau levels and the decrease of Aβ42 levels, two biological hallmarks of this disease. Tau concentrations were highest in AD and intermediate in FTD when compared to CTRL. The most interesting results were obtained by focusing on amyloid biomarkers as we found out in FTD a significant decrease of sAβPPβ, Aβ38, and Aβ40 levels. Aβ38 in particular was the most useful biomarker to differentiate FTD subjects from the CTRL population. Combining p-Tau and Aβ38 led us to correctly classifying FTD patients with sensitivity at 85% and specificity at 82%. Significant changes in amyloid biomarkers, particularly for Aβ38, are therefore seen in FTD. This could be quite useful for diagnosis purposes and it might provide additional evidence on the interrelationship between Tau and AβPP biology which understanding is essential to progress towards optimal therapeutic and diagnostic approaches of dementia.     

整合素β1、β3、β5基因在脑动静脉畸形和海绵状血管瘤中的表达

脑血管畸形是异常血管表型的病灶。脑动静肪畸形(AVM)和海绵状血管瘤是中枢神经系统最常见的血管畸形。目前对于这些疾病的发生和发展机制知之甚少。动静脉畸形和海绵状血管瘤中都可能存在血管的发生和生长,与疾病的发生和发展有关。血管的生长依赖于内皮细胞相互之间以及和细胞外间质的相互作用。内皮细胞的粘附性改变是这一过程中必不可少的步骤。整合素在脑内分布非常广泛,属于细胞粘附因子的一种,是介导细胞与细胞之间以及与细胞外间质之间粘附作用的主要因子。整合素β1、β3和β5都是影响血管生成的重要因子[1]。我们通过比较脑动静…     

L-β-N-oxalyl-α,β-diaminopropionic acid toxicity in motor neurons

The excitatory amino acid L-β-N-oxalyl-α,β-diaminopropionic acid (L-β-ODAP) in Lathyrus sativus L. is proposed as the causative agent of the neurodegenerative disease neurolathyrism. We investigated the effect of L-β-ODAP on [Ca2+]i handling, redox homeostasis, and cell death in rat spinal motor neurons. L-β-ODAP and L-glutamate triggered [Ca2+]i transients, which were inhibited by the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor blockers; 2,3-dioxo-6-nitro-1,2,3, 4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide and 1-naphthyl acetylspermine, the latter specifically blocking Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors. In addition, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide, and to a lesser extent 1-naphthyl acetylspermine, protected the neurons against cell death induced by L-β-ODAP or L-glutamate. Methionine and cysteine were also protective against neuronal cell death. We conclude that deregulation of [Ca2+]i homeostasis and oxidative stress contribute to motor neuron cell death in neurolathyrism.     

β-内啡肽与偏头痛

<正> 偏头痛是一种常见的非器质性头痛,其病因和发病机理较为复杂,多年来一直是人们研究的热点。本文就β-内啡肽与偏头痛的发病关系进行简要综述。 一、β-内啡肽的来源及作用 β-内啡肽(β-endorphin,β-EP)是继Hughes等1975年在猪脑中发现脑啡肽后.于1976年从骆驼垂体中分离出的α-内源性阿片肽(endogenous opioidpeptides,简称内阿片肽)。它由31个氨基酸组成,为     

多巴胺β-羟化酶缺乏症

多巴胺β-羟化酶缺乏症是由于基因异常使中枢神经系统或周围自主神经元合成去甲肾上腺素和肾上腺素障碍,临床上以直立性低血压、低血糖、低体温和血浆去甲肾上腺素/多巴胺比率明显小于1为特征。目前尚无特异疗法。     

转化生长因子β与脑积水

转化生长因子β(TGF:F-β)是一组由2个分子量为12.5kD的亚基通过两个二硫键连接而成的二聚体,与细胞膜上相应受体结合而发挥调节细胞生长、分化、免疫功能等多种生物学作用。脑积水由于脑脊液(CSF)分泌过多和(或)吸收障碍所致,临床上分为先天性和后天性,前者病因不明,后者多由于外伤、炎症、蛛网膜下腔出血(SAH)等引起网膜细胞增殖、蛛网膜下腔、蛛网膜粒及其表浅血管间隙、神经根周围间隙纤维增生,导致CSF分泌增多及吸收障碍。TGF-β在慢性脑积水发生过程中起重要作用,并逐渐受到人们的重视。     

人脑胶质瘤免疫抑制因子TGFβ2及TGFβ1的基因表达

目的 研究人脑胶质瘤主要免疫抑制因子转化生长因子TGFβ2及TGFβ1的基因表达与其胶质瘤恶性程度的关系。方法 采用Northern杂交,免疫组化和Western杂交法检测了50例胶质瘤,。3例恶笥胶质瘤体外细胞系和8例正常脑细胞TGFβ2的达表水平,同时检测其同型异构体TGFβ1的表达水平,结果 正常脑组织几无TGFβ2和TGFβ1表达,而胶质瘤均表达2．8和或5．1kb的TGFβ2mRNA片段和约25000u及30000u的蛋白,TGF和TGFβ1表达水平随肿瘤恶性程度增高而增高,结论 TGFβ2和TGFβ1表达水平与肿瘤恶性程度呈正相关,TGFβ2和TGFβ1可作为恶性胶质瘤免疫基因治疗的侯选基因。     

阿尔茨海默病中的Aβ研究进展

近年来由于分子生物学技术的应用推动了AD的病因研究 ,发现了几个AD的相关基因 ,其中最重要的是APP基因 ,由于APP蛋白断裂后产生具有毒性作用的Aβ。目前有许多研究者认为Aβ是AD的发病直接原因 ,本文就AD中的Aβ研究进展作一简要综述。     

阿尔茨海默病自身抗Aβ抗体对血浆Aβ水平的影响

目的通过比较有无自身抗Aβ抗体的阿尔茨海默病(AD)患者和年龄匹配的健康老年对照者(aNC)血浆Aβ水平之间差异,研究自身抗Aβ抗体对血浆Aβ水平的影响。方法113例AD患者和155例aNC的血浆对Tg2576小鼠大脑组织连续切片进行免疫染色,并进行组织淀粉样蛋白免疫反应(TAPIR)测定。随后,TAPIR阳性和阴性血浆分别与人工合成的Aβ40、Aβ42进行免疫沉降,免疫沉降物经过western blot检测分析其免疫特性。最后通过一种双抗体夹心的ELISA精确定量所有血浆的Aβ水平。结果(1)自身抗Aβ抗体无差异地频繁出现于AD患者(45．1%)和aNC中(41．3%)(P＞0．05),并在免疫沉降过程中表现出与Aβ40更强的亲和力。(2)两组TAPIR 和TAPIR-血浆的Aβ40和Aβ42水平比较均无显著性差异(P＞0．05)。结论自身抗Aβ抗体不足以影响血浆Aβ水平,人类抗Aβ抗体产生和作用机制可能有别于转基因AD动物模型。     

β淀粉样蛋白受体研究进展

β淀粉样蛋白在阿尔茨海默病发病中的作用受到大多数学者的确认,但β淀粉样蛋白的细胞毒性机制未明。近年来β淀粉样蛋白的受体研究取得了很大的进展,本文就β淀粉样蛋白受体研究现状作一介绍。     

转化生长因子β与胶质瘤

转化生长因子β是一大类多功能的细胞因子,与细胞膜上相应的三种受体结合而发挥作用。其表达量与胶质瘤的病理分级是否有关尚存在争议,但它却是公认的免疫抑制剂,可通过多种途径抑制宿主的全身和局部免疫反应。转化生长因子β还可参与促进胶质瘤的血管形成,其对胶质瘤侵袭性的影响则具有量的依赖性。以转化生长因子β为靶点针对胶质瘤的治疗正受到人们的关注。     

TGF-β与中枢神经系统疾病

TGF－p（Transforminggrowthfactor步转移牛长因子p）是一种可在体内或体外由各种正常或已转化的细胞产失的多功能调节肽u已发现，TGF－p家族由6种结构相关的高度同源的分子组成，但哺乳动物中仅发现TGF－pl、p。、日3等三种。TGF－p在正常神经组织中表达水平低．病理情况下可见高水平表达，在中枢神经系统疾病中发挥保护或致病作用。一、TGF－p在中枢神经系统中的正常表达与功能1．TGF－p的表达：中枢神经系统的神经元、星形细胞、小政质细胞及少突胶质细胞等均可产生TGF一人所有脑区，包括大脑皮质、海马、纹状体、小脑、脑子及…     

阿尔茨海默病与β-淀粉样蛋白（Aβ）寡聚体损伤突触功能

神经突触具有高度可塑性,突触的形成和重塑是神经元活动依赖性的,是学习记忆、认知功能的基础。包括阿尔茨海默病（AD）在内的多种表现出认知缺陷的神经疾病,均存在突触结构或者功能的异常。AD病程缓慢,临床早期表现为单纯的记忆功能损伤,证据显示此症状是海马突触效能发生微细改变所致。近20年来,大量实验证实β-淀粉样蛋白（Aβ）寡聚体能够弥散到突触间隙,是最早的损害突触完整性和可塑性的因素。多种不同来源的Aβ寡聚体（包括体外合成的,细胞分泌的,AD转基因动物和AD患者脑内的）,能够破坏海马脑片或者动物在体的长时程增强效应（Long-term potentiation, LTP）,降低器官型培养的海马脑片的树突棘密度,损害啮齿类动物的认知和记忆功能。AD患者皮质中可溶性Aβ（包括寡聚体）的水平与认知功能呈强相关性。而不可溶的淀粉样沉淀可能是作为具有突触毒性的寡聚体的一种储备。     

Communicating hydrocephalus in rodents treated withβ,β′-iminodipropionitrile (IDPN)

Summary ,-Iminodipropionitrile (IDPN), a neurotoxic compound known to induce swellings in the proximal internodes of sensory and motor axons in several parts of the central nervous system (CNS), was also found to cause hydrocephalus in rats and guinea pigs. In both species, ventricular dilatation was observed within 1 week following a single i.p. injection of IDPN. While in rats the severity of hydrocephalus correlated with dose and duration of IDPN exposure, in guinea pigs studies with high doses yielded inconclusive results, and no significant temporal correlation was noted. Parallel investigations with another peurotoxic agent, acrylamide, in rats, and with IDPN in cats failed to demonstrate any change in size and shape of the cerebrospinal fluid (CSF) pathways. No signs of spontaneously occurring hydrocephalus were found in control animals. In both rats and guinea pigs intoxicated with IDPN, macroscopic and microscopic findings were consistent with the diagnosis of communicating hydrocephalus. Treatment of hydrocephalic rats with acetazolamide (500 mg/kg) markedly attenuated ventricular distention, suggesting that an overproduction of CSF by the choroid plexus is responsible for the communicating hydrocephalus following IDPN intoxication.A preliminary report of this work has been presented at the Second International Conference on Neurotoxicology of Selected Chemicals, Chicago, IL, USA, September 1983Supported by USPHS NIH grant NS-11948     

β淀粉样蛋白与细胞因子S100β表达的相关性研究及其意义

目的　研究大鼠脑内Ａβ４０的沉积与细胞因子Ｓ１００β表达的关系。方法　我们将Ａβ４０定向注射于大鼠的双侧海马,采用免疫组化方法观察了Ｓ１００β的表达。结果　Ｓ１００β免疫组化显示,Ａβ４０处理的大鼠海马区域有细胞因子Ｓ１００β的表达,而在生理盐水对照组的大鼠海马区未出现Ｓ１００β的阳性表达。结论　结果提示Ａβ４０可诱导大鼠海马Ｓ１００β表达。在超过生理性效应的阈值水平之上慢性持续性表达时,Ｓ１００β可能是一种重要的致病因子,具有神经毒性效应,参与Ａｌｚｈｅｉｍｅｒ病的病理活动。Ａβ４０可能是一种重要的病理性刺激因素。     

β淀粉样蛋白与细胞因子S100β表达的相关性研究及其 …

目的 研究大鼠脑内Ａβ４０的沉积与细胞因子Ｓ１００β表达的关系。方法 我们将Ａβ４０定向注射于大鼠的双侧海马，采用免疫组化方法观察了Ｓ１００β的表达。结果 Ｓ１００β免疫组化显示，Ａβ４０处理的大鼠海马区域有细胞因子Ｓ１００β的表达，而在生理盐水对组照组的大鼠海马区未出现Ｓ１００β的阳性表达。结论 结果提示Ａβ４０可诱导大鼠海马Ｓ１００β表达。在超过生理性效应的阈值水平之上慢性持续性表达时，Ｓ１０     

The amyloid-β₄₂ proxy, amyloid-β(25-35), induces normal human cerebral astrocytes to produce amyloid-β₄₂

Amyloid-β (Aβ) peptides in the brain of patients with Alzheimer's disease (AD) assemble into various aggregation forms that differ in size, structure, and functional properties. Previous studies have shown that Aβ binds to nicotinic acetylcholine receptors (nAChRs) and activates signaling cascades that result in the disruption of synaptic functions. These findings suggest a possible link between impaired cholinergic neurotransmitter function in AD and Aβ pathogenesis. However, it is not yet known how the different Aβ assemblies interact with specific nAChR subtypes. In the present study, we demonstrate that neurotoxicity in neuronal cells in culture induced by fibrillar Aβ(1-40) is prevented through an α7 nAChR-dependent mechanism. The α7 nAChR agonists varenicline and JN403 increased binding of the amyloid ligand [3H]PIB to fibrillar Aβ in AD frontal cortex autopsy tissue. This suggests that the presence of nAChR agonists may inhibit interaction of Aβ with α7 nAChRs and prevent the formation of Aβ/α7 nAChR complexes. This interaction was confirmed in binding assays with [12?I]Aβ(1-40) and α7 nAChRs in autopsy brain tissue homogenates from the frontal cortex. The functional effects of Aβ fibrils and oligomers on nAChRs were examined by measuring intracellular calcium ([Ca(2+)](i) levels. Oligomeric, but not fibrillar Aβ(1-40), increased [Ca(2+)](i) in neuronal cells, and this effect was attenuated by varenicline. Our findings demonstrate that fibrillar Aβ exerts neurotoxic effects mediated partly through a blockade of α7 nAChRs, whilst oligomeric Aβ may act as a ligand activating α7 nAChRs, thereby stimulating downstream signaling pathways.     

Pretreatment of PC12 Cells with 17β-estradiol Prevents Aβ-Induced Down-Regulation of CREB Phosphorylation and Prolongs Inhibition of GSK-3β

It is believed that estrogen protects neurons against various toxicities like that from amyloid β (Aβ) in Alzheimer’s disease (AD). In the present study, we investigated the effects of Aβ_1–42 on the activities of cyclic-AMP response element-binding protein (CREB) and glycogen synthase kinase-3β (GSK-3β), two key proteins associated with learning and memory, and the effects of 17β-estradiol on Aβ_1–42-induced changes of CREB and GSK-3β in PC12 cells. We found that Aβ_1–42 induced a decrease in phosphorylation of CREB at Ser133 (CREB pS133) and caused a transient (30 min) up-regulation of the inhibitory GSK-3β phosphorylation at Ser9 (GSK-3β pS9), followed by down-regulation of GSK-3β pS9. Pretreatment of 17β-estradiol is needed for its protection against Aβ_1–42-induced changes of CREB. The protective role of 17β-estradiol against Aβ_1–42-induced down-regulation of CREB pS133 was abolished by the mitogen-activated protein kinase (MAPK) pathway inhibitor U0126. Furthermore, 17β-estradiol also prolonged the up-regulation of GSK-3β pS9 for at least 8 h. However, this action of 17β-estradiol was abrogated by PKA inhibitor H-89, AKT inhibitor LY294002, and MAPK inhibitor U0126. These results suggest that, while the protection of 17β-estradiol on CREB is MAPK dependent, its effect on GSK-3β integrates several pathways. These studies provide new insights into the role of estrogen in memory and AD.