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。     

阿尔茨海默病动物模型的研究现状

阿尔茨海默病(Alzheimer’s Disease,AD)是一种病因不明的脑部退行性疾病。理想的AD动物模型,对研究该病的发病机制及治疗具有重要意义。近年来对于AD动物模型的研究取得了很大进展,本文就目前AD动物模型的研究现状做一综述。     

老年性痴呆动物模型研究进展

老年性痴呆 (Alzheimersdisease,AD)是以老年斑和神经纤维缠结为特征的一种进行性、退行性神经系统疾病。AD动物模型的研究可大大促进AD病因、发病机制及药物筛选的研究 ,是深入开展AD研究的必要条件之一。损伤性、自然衰老动物和复合型动物模型能够复制出认知缺损等表现 ,但缺乏AD的特征性病变。SAM P/ 8是相对理想的模型。转基因小鼠是目前研究的热点 ,为在体研究AD的特定发病基因及其代谢产物提供了新的载体。随着AD治疗学由对症治疗转向对因治疗 ,AD模型也应顺应这一发展。     

散发性阿尔茨海默病动物模型研究进展

阿尔茨海默病(Alzheimer's disease,AD)是一种中枢神经退行性疾病,是最常见的痴呆类型。阿尔茨海默病多为散发性,目前暂无延缓疾病进程的药物上市。散发性阿尔茨海默病(sporadic Alzheimer's disease,s AD)动物模型的缺乏可能是主要原因之一。因此,研发散发性阿尔茨海默病动物模型非常有意义。本文现就散发性阿尔茨海默病动物模型的制作、病理特征及其可能机制加以归纳总结。此外,我们还对今后散发性阿尔茨海默病动物模型的发展做了探讨,以期对相关研究工作者的研究有所裨益。     

阿尔茨海默病动物模型研究进展

目的阿尔茨海默病(Alzhei mer's disease,AD)动物模型的研究,对本病的防治具有重要意义。方法综述近年来发表的国内外文献33篇。结果与方法本文综述了AD的动物模型近几年的研究成果,从(淀粉样蛋白、胆碱能损伤和转基因动物等几个方面讨论并比较这些动物模型在复制AD病理和行为改变方面的优点和不足。     

早老年性痴呆(AD)动物模型研究进展

早老年性痴呆(AD)的动物模型研究,对于寻找治疗该病的有效药物及阐明病理形成具有重要意义。近年来,众多学者在各自研究领域依据AD病因病理特点,制备多种动物模型。本文综述了胆碱能损伤、谷氨酸能损毁、脂褐质蓄积、代谢紊乱、海马神经细胞损伤、衰老、转基因动物等AD痴呆模型进展。     

老年性痴呆动物模型研究进展

老年性痴呆 (Alzheimersdisease ,AD )是一种进行性的神经退行性疾病 ,临床主要表现为中枢认知功能障碍 ,老年斑、淀粉样蛋白沉积及神经元纤维缠结 (NFT)是其脑部主要的病理学特征。由于AD的发病机制尚不清楚 ,给AD模型动物的研制带来了很大困难。自然衰老动物模型、损毁模型、脑室注射模型及自身免疫模型虽表现有中枢学习记忆功能的衰退 ,但缺乏AD脑内特征性的病理学变化。转基因模型虽然是十分有希望的模型 ,但目前的转基因模型尚不能全面反映AD的特征。因此 ,迄今为止还没有一个能够准确反应AD特征的理想的动物模型。比较而言 ,SAMP8是一个较好的AD替代模型 ,它既有AD学习记忆功能障碍的特征 ,又有部分AD病理学的特征。目前自身免疫模型和转基因模型已成为AD模型研究的新热点。研究并建立可靠的AD动物模型对于探明AD的发病机制以及防治药物的研究均具有重要的意义     

阿尔茨海默病患者细胞免疫功能的变化

阿尔茨海默病（alzheimer’s disease，AD）的发病较为复杂，目前病因不明。近年来发现免疫反应参与了其病理生理过程，国内外许多学者对此进行了大量研究。特别是AD与免疫的关系日益受到人们广泛的关注，来自实验及临床的研究资料提示，AD动物模型及AD患者的外周免疫功能出现异常，证实AD发生与免疫紊乱有关。     

2009-2018年国家自然科学基金在防治阿尔茨海默病药物药理学研究领域资助项目分析

2009-2018年间,在防治阿尔茨海默病(AD)药物药理学研究领域的国家自然科学基金(NSFC)资助项目增加显著。分析发现,AD防治药物研究逐步由围绕β淀粉样蛋白(Aβ)级联学说和tau蛋白异常修饰学说的相关机制靶点,过度到针对自噬和炎症、表观遗传修饰、肠道菌群失衡等的新机制和新靶点。NSFC针对AD动物模型资助的研究也由早期的Aβ动物模型,逐渐过度为综合考虑AD自身发病因素和AD特征或危险因素(如胰岛素耐受、炎症和自然衰老等)的动物模型。综合看,我国目前AD基础研究能紧跟国际前沿和热点问题,但仍缺乏连续、深入的研究和有创新性、有独特构思的工作。NSFC在AD防治药物资助策略上更应鼓励学科交叉和临床转化,使其成为一个突破口并带领多领域的后续发展。     

特应性皮炎动物模型与免疫学机制及中药治疗的研究进展

特应性皮炎(atopic dermatitis,AD)是一种由遗传、环境、皮肤屏障功能及外界变应性等因素引起的慢性炎症性皮肤病,并且涉及不同类型细胞相关因子以及通路的相互作用,目前对该病病因尚待进一步研究。本文对AD的动物模型、免疫学机制以及近几年中药治疗及其研究现状进行综述。     

阿尔采末病模式生物研究进展

随着家族性阿尔采未病的研究的发展,人们建立了很多阿尔采末病的模式生物模型,如线虫、果蝇和小鼠模型,这些模型是研究阿尔采末病神经病理变化非常有效的模型。本文主要介绍了各种转基因阿尔采末病模型的研究特点,以及利用这些动物模型寻找新的神经保护药物和药物治疗靶点的研究进展。     

AD细胞模型的建立及评价方法研究进展

细胞模型是研究阿尔茨海默病(Alzheimer’s disease,AD)的有效方法之一。近年来,建立体外AD细胞模型来模拟AD的发病机制已成为学者的关注点。该文通过整理近年AD细胞建模的相关文献,深入探讨AD的发病机制,总结并系统分析AD细胞模型建立方法、评价指标及模型特点,以期对AD细胞模型合理构建及深入研究提供思路与借鉴。     

FLZ attenuates learning and memory deficits via suppressing neuroinflammation induced by LPS in mice

Alzheimer's disease (AD) is the most common neurodegenerative disorder in which neuroinflammation plays an important role. FLZ is a novel synthetic derivative of natural squamosamide. Previous studies demonstrated that FLZ had neuroprotective effects on AD models and showed strong anti-inflammatory property in Parkinson's disease models. However, whether the neuroprotective effects of FLZ on AD are associated with its anti-inflammatory property is still not fully elucidated. In this study, we aimed to investigate the ability of FLZ in modulating inflammation. The results showed that FLZ significantly improved memory deficits and alleviated neuronal damage as well as neuronal loss in the hippocampus of mice intracerebroventricular injected with lipopolysaccharide (LPS). Mechanistic studies revealed that the neuroprotective effects of FLZ were due to the suppression of neuroinflammation induced by LPS, as indicated by inactivation of astrocytes and microglia, reduced production of tumor necrosis factor-α, interleukin-1β, and nitric oxide, as well as decreased expression of cyclooxygenase-2 and inducible nitric oxide synthase. The beneficial effects of FLZ on AD were further supported by the finding that FLZ attenuated β-amyloid production through inhibiting β-amyloid precursor protein cleaving enzyme 1 expression. These results suggested that anti-inflammatory agent could be useful for the treatment of AD.     

抗阿尔茨海默病药物非临床药效学评价体系的探索

阿尔茨海默病(Alzheimer’s disease, AD)是引发老年人痴呆的最常见的神经退行性疾病。目前, AD的发病机制尚不明确,已上市的药物全部为对症治疗药物,无法延缓或逆转疾病的进程,同时在研药物面临严峻的临床转化难题。因此,围绕AD展开新药研发,解决未被满足的临床需求具有重大的社会意义和经济价值。本文结合了近年来国内外抗AD药物的研发进展,主要从动物模型和药效评价指标两个方面对抗AD药物非临床药效学评价体系进行归纳总结,以期为抗AD药物的非临床开发提供参考。     

Rodent models for Alzheimer’s disease drug discovery

Introduction: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, leading to dementia. Histopathological hallmarks are represented by aggregates of beta-amyloid peptide (Aβ) in senile plaques and deposition of hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Rare forms of early onset familial Alzheimer’s disease are due to gene mutations. This has prompted researchers to develop genetically modified animals that could recapitulate the main features of the disease. The use of these models is complemented by non-genetically modified animals.

Areas covered: This review summarizes the characteristics of the most used transgenic (Tg) and non-Tg models of AD. The authors have focused on models mainly used in their laboratories including amyloid precursor protein (APP) Tg2576, APP/presenilin 1, 3xAD, single h-Tau, non-Tg mice treated with acute injections of Aβ or tau, and models of physiological aging.

Expert opinion: Animal models of disease might be very useful for studying the pathophysiology of the disease and for testing new therapeutics in preclinical studies but they do not reproduce the entire clinical features of human AD. When selecting a model, researchers should consider the various factors that might influence the phenotype. They should also consider the timing of testing/treating animals since the age at which each model develops certain aspects of the AD pathology varies.     

石杉碱甲改善阿尔采末病相关线粒体功能损伤及潜在分子机制

阿尔采末病(AD)是一种常见的神经退行性疾病,目前临床上应用最广泛的AD治疗药物是乙酰胆碱酯酶抑制剂(AChEI)。石杉碱甲是我国自主研发的AChEI,近期研究显示除了胆碱酯酶抑制作用之外,石杉碱甲在大脑中动脉栓塞大鼠、APP/PS1转基因小鼠及β-淀粉样蛋白损伤的离体线粒体等多种模型中有显著的线粒体功能保护作用。本文对线粒体在AD发生发展中的作用和石杉碱甲对AD相关线粒体功能损伤的保护作用作一综述,并探讨其潜在的分子机制。     

毒扁豆碱对老年痴呆大鼠的空间记忆能力的影响

目的:探讨毒扁豆碱对老年痴呆大鼠的空间记忆能力的影响,为老年痴呆病人的临床治疗提供新的治疗思路。方法:健康成年雄性大鼠48只,随机分为痴呆组、毒扁豆碱对照组、毒扁豆碱治疗组、空白对照组。运用大鼠穹窿-海马切断术建立痴呆模型,术后第8天开始腹腔注射毒扁豆碱,连续1周,然后各组进行Morris水迷宫测试。结果:空间探索实验结果显示,大鼠各象限游泳距离占总距离百分率和跨越各象限平台相应位置次数占总次数百分率,毒扁豆碱治疗组均有明显提高。定位航行实验提示毒扁豆碱处理后的痴呆大鼠寻找水下平台时间明显缩短。结论:痴呆大鼠经过毒扁豆碱治疗后,空间记忆能力出现明显好转,提示毒扁豆碱对痴呆大鼠具有一定的改善作用。     

The value and limitations of transgenic mouse models used in drug discovery for Alzheimer's disease: an update

Introduction: The exponential growth in the world's aged population has increased pressure on drug discovery efforts to identify innovative therapies for Alzheimer's disease (AD). The long and uncertain clinical trial path utilized to test the potential efficacy of these novel agents is challenging. For these and other reasons, there has been an explosion in the generation and availability of transgenic mouse models that mimic some, but not all aspects of AD. The largely overwhelmingly positive results obtained when testing potential clinical agents in these same animal models have failed to translate into similar positive clinical outcomes.

Areas covered: This review discusses the value and limitations associated with currently available transgenic mouse models of AD. Furthermore, the article proposes ways in which researchers can better characterize pharmacodynamic and pharmacokinetic endpoints to increase the success rate for novel therapies advancing into clinical development. Lastly, the author discusses ways in which researchers can supplement, expand and improve transgenic mouse models used in AD drug discovery.

Expert opinion: The use of transgenic mouse models that recapitulate various aspects of AD has expanded our knowledge and understanding of disease pathogenesis immensely. Further success in testing and translating novel therapies from animal models into bona fide medicines would be enhanced by i) the availability of better models that more fully recapitulate the disease spectrum, ii) defining and measuring standardized endpoints that display a pharmacodynamic range, iii) building and including translatable biomarkers and iv) including novel endpoints that would be expected to translate into clinically beneficial outcomes.