趋化因子参与阿尔茨海默病的研究进展

趋化因子在阿尔茨海默病(Alzheimer's disease,AD)的发病机制中发挥多重作用。AD是一种中枢神经系统的慢性炎症性疾病,其神经病理学特征包括神经原纤维缠结(neurofibrillary tangles,NFT)、β淀粉样蛋白(amyloid beta protein,Aβ)斑块、神经炎症和神经元突触丢失。趋化因子通过激活或调节炎症细胞和神经胶质细胞参与AD的病理机制,发挥了促炎和抗炎双重作用。AD患者血清、脑脊液和脑组织中的趋化因子水平发生相应的变化。该综述总结了趋化因子及其受体在AD中的生物活性以及变化规律,为临床治疗AD提供新的策略。     

内源性大麻素系统与老年性痴呆

老年性痴呆即阿尔茨海默病（Alzheimer’Sdisease,AD）是一种慢性进行性的神经退行性病变,其特征性病理改变为β-淀粉样蛋白（β-amy-loidpeptide,Aβ）沉积形成的细胞外老年斑和tau蛋白过度磷酸化形成的神经细胞内神经原纤维缠结,以及神经元丢失伴随胶质细胞增生等。最近的研究发现内源性大麻素系统对AD的病程有预防治疗作用,主要基于其对神经的保护作用和抗炎功效。本文综述了内源性大麻素对AD的保护作用的几个方面,旨在为AD的治疗开辟新的策略和思路。     

阿尔茨海默病与胆碱酯酶

胆碱酯酶 ( Ch E)在阿尔茨海默病 ( Alzheimer's,AD)的形成、诊断及治疗中起着重要的作用 :在乙酰胆碱酯酶 ( ACh E)的启动及丁酰胆碱酯酶 ( BCh E)的协助下 ,β-淀粉样蛋白 ( A- β)与载脂蛋白 E结合并沉积于脑内 ,形成老年斑及神经原纤维缠结 ;应用胆碱酯酶抑制剂治疗 AD有一定效果 ;根据胆碱酯酶结构 ,利用计算机模拟技术可设计合成新型抑制 ACh E药物     

β-淀粉蛋白的研究进展

茨海默病(AD)是老年人最常见的中枢神经系统退行性疾病,其主要病理变化是老年斑、神经原纤维缠结和神经元缺失等.β-淀粉样蛋白(β-amyloid protein,AB)是老年斑的主要成分,本文就AB的来源、分子结构特点、毒性作用机理及其靶位治疗AD等方面研究进展综述如下.     

阿尔兹海默病的表观遗传学机制及相关药物研究

阿尔茨海默病(AD)是一种神经退行性疾病,以神经元减少、老年斑形成及神经原纤维缠结等为特征,是老年痴呆症的最常见原因。人们对表观遗传学在AD发病中的机制已经做了许多研究,如相关基因的甲基化、组蛋白乙酰化,但具体机制仍未完全明确。本文对AD的表观遗传学机制及相关药物研究进行综述,为AD表观遗传学治疗药物的研发提供新的方向。     

阿尔茨海默病综合治疗的探讨

阿尔茨海默病(Alzhei mer's disease,AD)是一种原因未明的、常见的中枢神经系统变性疾病,主要侵犯大脑皮质神经元。表现为进行性智能减退,以严重的高级认知功能和记忆功能障碍为临床特征。其发病机制是蛋白质的凝固、聚合形成特征性的神经原纤维缠结(NFTs)和老年斑(SPs)。     

氧化应激在阿尔茨海默病中的作用及相关药物研究进展

阿尔茨海默病(Alzheimer’s disease,AD)是以进行性认知功能障碍和记忆力损害为主的中枢神经系统的退行性疾病,其发病机制十分复杂。氧化应激可损伤细胞内多种生物大分子。在AD患者脑中,脂质、蛋白质、DNA、RNA和糖类都存在过氧化形式。氧化应激也参与了形成老年斑、神经原纤维缠结以及神经元细胞凋亡。此外,氧化应激还与AD发病机制的神经炎症和线粒体功能异常有关联,与其共同加剧了AD的发生。具有强抗氧化活性的生物活性分子（如褪黑素和吡咯喹啉醌）有望成为很有前途的以氧化应激为靶点的抗AD治疗药物。     

氧化应激在阿尔茨海默病中的作用及相关药物研究进展

阿尔茨海默病(Alzheimer’s disease,AD)是以进行性认知功能障碍和记忆力损害为主的中枢神经系统的退行性疾病,其发病机制十分复杂。氧化应激可损伤细胞内多种生物大分子。在AD患者脑中,脂质、蛋白质、DNA、RNA和糖类都存在过氧化形式。氧化应激也参与了形成老年斑、神经原纤维缠结以及神经元细胞凋亡。此外,氧化应激还与AD发病机制的神经炎症和线粒体功能异常有关联,与其共同加剧了AD的发生。具有强抗氧化活性的生物活性分子（如褪黑素和吡咯喹啉醌）有望成为很有前途的以氧化应激为靶点的抗AD治疗药物。     

氧化应激在阿尔茨海默病中的作用及相关药物研究进展

阿尔茨海默病(Alzheimer’s disease，AD)是以进行性认知功能障碍和记忆力损害为主的中枢神经系统的退行性疾病，其发病机制十分复杂。氧化应激可损伤细胞内多种生物大分子。在AD患者脑中，脂质、蛋白质、DNA、RNA和糖类都存在过氧化形式。氧化应激也参与了形成老年斑、神经原纤维缠结以及神经元细胞凋亡。此外，氧化应激还与AD发病机制的神经炎症和线粒体功能异常有关联，与其共同加剧了AD的发生。具有强抗氧化活性的生物活性分子（如褪黑素和吡咯喹啉醌）有望成为很有前途的以氧化应激为靶点的抗AD治疗药物。     

氧化应激在阿尔茨海默病中的作用及相关药物研究进展

阿尔茨海默病(Alzheimer’s disease，AD)是以进行性认知功能障碍和记忆力损害为主的中枢神经系统的退行性疾病，其发病机制十分复杂。氧化应激可损伤细胞内多种生物大分子。在AD患者脑中，脂质、蛋白质、DNA、RNA和糖类都存在过氧化形式。氧化应激也参与了形成老年斑、神经原纤维缠结以及神经元细胞凋亡。此外，氧化应激还与AD发病机制的神经炎症和线粒体功能异常有关联，与其共同加剧了AD的发生。具有强抗氧化活性的生物活性分子（如褪黑素和吡咯喹啉醌）有望成为很有前途的以氧化应激为靶点的抗AD治疗药物。     

Current experimental therapy for Alzheimer's disease

In the past decade, enormous efforts have been devoted to understand the genetics and molecular pathogenesis of Alzheimer's disease (AD), which has been transferred into extensive experimental approaches aimed at reversing disease progression. The trend in future AD therapy has been shifted from traditional anti-acetylcholinesterase treatment to multiple mechanisms-based therapy targeting amyloid plaques formation and amyloid peptides (Abeta)-mediated cytotoxicity, and neurofibrillary tangles generation. This review will cover current experimental studies with the focus on secretases-based drug development, immunotherapy, and anti-neurofibrillary tangles intervention. The outcome of these on-going studies may provide high hope that AD can be cured in the future.     

M1胆碱受体激动剂治疗阿尔茨海默病的研究进展

阿尔茨海默病(Alzheimer disease，AD)是一种以胆碱能神经元进行性退变、老年斑和神经元缠结为病理特征的神经退行性疾病。尽管AD发病机制尚未阐明，但β淀粉样肽沉积和tau蛋白磷酸化与胆碱能神经退变的恶性循环(vicious cycle)无疑是造成AD的重要病理机制之一。大量研究表明胆碱能神经突触后膜的M1受体的数目在整个病程中变化不大，M1受体选择性激动剂不但可以直接补偿胆碱能的功能，而且可以调节β淀粉样前体蛋白代谢和降低tau蛋白的过度磷酸化，有助于打破这一恶性循环，改善AD的学习记忆功能并延缓病情的发展。因此M1胆碱受体激动剂被认为是最有前途的治疗AD药物之一。目前Xanomeline、Sabcomeline等具有相对选择性M1受体激动剂业已进入新药临床试验阶段。     

Disease modifying approaches for Alzheimer's pathology

Alzheimer's disease (AD) is the most common age-associated neurodegenerative disease in the world. The major neuropathological features of AD are synaptic loss, neuronal loss, neurofibrillary tangles and the deposition of amyloid-beta (Abeta) as plaques and in cerebral blood vessels. Numerous Abeta targeting therapeutic approaches have been shown to prevent amyloid deposition and resulting in cognitive improvement in transgenic mouse models of AD. Some of these approaches are currently in early clinical trials. It remains to be seen if these approaches will be proven effective in patients. Future anti-AD therapies will likely be multi-modal and individually tailored depending on the patient's immune status, genetic background and their amyloid burden, as determined by imaging studies using Abeta specific labeling ligands. Pre-clinical data suggests that it will be much more feasible to prevent AD related pathology, then to clear existing pathology, making early diagnosis critically important.     

Peptides for therapy and diagnosis of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with devastating effects. The greatest risk factor to develop AD is age. Today, only symptomatic therapies are available. Additionally, AD can be diagnosed with certainty only post mortem, whereas the diagnosis "probable AD" can be established earliest when severe clinical symptoms appear. Specific neuropathological changes like neurofibrillary tangles and amyloid plaques define AD. Amyloid plaques are mainly composed of the amyloid-βpeptide (Aβ). Several lines of evidence suggest that the progressive concentration and subsequent aggregation and accumulation of Aβ play a fundamental role in the disease progress. Therefore, substances which bind to Aβ and influence aggregation thereof are of great interest. An enormous number of organic substances for therapeutic purposes are described. This review focuses on peptides developed for diagnosis and therapy of AD and discusses the pre- and disadvantages of peptide drugs.     

Cyclooxygenase-1 and -2 in the different stages of Alzheimer's disease pathology

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of beta amyloid (Abeta) protein and the formation of neurofibrillary tangles. In addition, there is an increase of inflammatory proteins in the brains of AD patients. Epidemiological studies, indicating that non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk of developing AD, have encouraged the study on the role of inflammation in AD. The best-characterized action of most NSAIDs is the inhibition of cyclooxygenase (COX). The expression of the constitutively expressed COX-1 and the inflammatory induced COX-2 has been intensively investigated in AD brain and different disease models for AD. Despite these studies, clinical trials with NSAIDs or selective COX-2 inhibitors showed little or no effect on clinical progression of AD. The expression levels of COX-1 and COX-2 change in the different stages of AD pathology. In an early stage, when low-fibrillar Abeta deposits are present and only very few neurofibrillary tangles are observed in the cortical areas, COX-2 is increased in neurons. The increased neuronal COX-2 expression parallels and colocalizes with the expression of cell cycle proteins. COX-1 is primarily expressed in microglia, which are associated with fibrillar Abeta deposits. This suggests that in AD brain COX-1 and COX-2 are involved in inflammatory and regenerating pathways respectively. In this review we will discuss the role of COX-1 and COX-2 in the different stages of AD pathology. Understanding the physiological and pathological role of cyclooxygenase in AD pathology may facilitate the design of therapeutics for the treatment or prevention of AD.     

A survey of peptides with effective therapeutic potential in Alzheimer's disease rodent models or in human clinical studies

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common cause of dementia. Today, only palliative therapies are available. The pathological hallmarks of AD are the presence of neurofibrillary tangles and amyloid plaques, mainly composed of the amyloid-β peptide (Aβ), in the brains of the patients. Several lines of evidence suggest that the increased production and/or decreased cleavage of Aβ and subsequent accumulation of Aβ oligomers and aggregates play a fundamental role in the disease progress. Therefore, substances which bind to Aβ and influence aggregation thereof are of great interest. A wide range of Aβ binding peptides were investigated to date for therapeutic purposes. Only very few were shown to be effective in rodent AD models or in clinical studies. Here, we review those peptides and discuss their possible mechanisms of action.     

G蛋白介导的信号传递在阿尔采末病中的功能变化

阿尔采末病 (AD)是一种神经退行性疾病 ,病理特点主要有 β 淀粉样蛋白的沉积和神经纤维缠结的形成。一直以为AD脑中神经元功能受损与突触后受体变化无关 ,但近来越来越多的证据表明中枢神经递质受体 /G蛋白介导的腺苷酸环化酶和磷酯酰肌醇水解信号转导途径在AD病程中均受到不同程度的损害 ,这亦解释了神经递质替代疗法在治疗AD中疗效有限的原因 ,同时为进一步研究和开发防治AD新药提供新思路     

阿尔茨海默病和轻度认知障碍常用实验动物模型的初步评价

阿尔茨海默病(AD)是一种典型的以进行性认知障碍和行为损害为特征的中枢神经退行性疾病,病理表现主要有细胞外淀粉样蛋白沉积、细胞内神经纤维缠结以及神经元丢失等。轻度认知障碍(MCI)是介于正常认知和AD之间的一种认知缺损状态,MCI具有转化为AD的高度危险性。以往大多通过建立具有临床AD特征的动物模型进行机制研究、药物筛选以及新药研发等,近年来,有研究者尝试建立具有临床MCI特征的动物模型,试图从MCI阶段进行早期干预,从而有效预防AD的发生。AD实验动物模型有多种类型,MCI研究模型应区别于AD模型。该文在对AD和MCI的特点进行较系统介绍的基础上,从模型建立的角度对常用AD和MCI实验动物模型进行了总结和初步评价,尝试为开展AD和MCI的研究提供建议。     

Amyloid aggregation inhibitors

Amongst the 4,700 presentations at the 215th National Meeting of the American Chemical Society (ACS), were fourteen research papers on Alzheimer's disease (AD) and related issues. The dementia associated with AD is a progressive and common neuro-degenerative disorder producing widespread brain destruction, with no curative therapies. The brains of AD patients have an abundance of amyloid plaques and neurofibrillary tangles. The major protein component of the amyloid plaques is the beta-peptide that exists in two predominant forms: the shorter, 40-residue beta(1-40), and the longer, 42-residue beta(1-42). Recent genetic studies have established that amyloid deposition, particularly by the longer beta(1-42), is directly linked to early onset cases of AD. As a result, major research efforts are focused on uncovering effective therapeutic strategies to prevent or slow down the aggregation and the associated precipitation of the beta-peptide into amyloid. In the amyloid deposits, the beta-peptide adopts a beta-sheet structure which is proposed to be neurotoxic.     

Anti-inflammatory and Immune Therapy for Alzheimer's Disease: Current Status and Future Directions

From the initial characterizations of inflammatory responses in Alzheimer’s disease (AD) affected brains, namely the demonstration of activated microglia and reactive astrocytes, complement system activation, increased production of proinflammatory cytokines, and evidence for microglial-produced neurotoxins, there was hope that reducing inflammation might be a feasible treatment for this memory-robbing disease. This hope was supported by a number of epidemiology studies demonstrating that patients who took non-steroidal anti-inflammatory drugs had significantly lower risk of developing AD. However, clinical trials of anti-inflammatories have not shown effectiveness, and in recent years, the concept of immune therapy has become a treatment option as animal studies and clinical trials with Aβ vaccines have demonstrated enhanced amyloid removal through stimulation of microglial phagocytosis.