阿尔茨海默病免疫治疗研究进展

AD已成为威胁人类晚年健康的一大隐患,其发病率有逐年上升之趋势,给社会带来沉重负担,对该病的研究显得非常紧迫.自1999年Schenk等人首次报道了Aβ肽疫苗免疫接种AD转基因小鼠取得的进展后,免疫治疗作为AD预防和研究的全新领域被开辟出来,并成为近年来研究的焦点之一.本文就该病的免疫治疗及疫苗研究进展作一综述.     

阿尔茨海默病治疗性单链抗体的研究进展

阿尔茨海默氏病(AD)的免疫治疗方法自提出以来尽管经历了些许挫折,但经过研究人员多年不懈努力,已经得到了快速发展。其中针对β-淀粉样蛋白的单链抗体(scFv)已经成为AD治疗性抗体中最有希望实现突破的一种策略,并正在成为免疫治疗AD的抗体药物研究的前沿和热点。本文概述了AD治疗性scFv的来源优势,对AD致病抗原识别与结合的特点,改善AD病理特征的效应以及与其效应相关的脑转运机制和体外亲和力成熟过程和结构因素,旨在为相关研究提供理论线索和发展思路。     

阿尔茨海默病的免疫治疗

阿尔茨海默病(AlzheimerIsdisease,AD)是一种中枢神经系统退行性疾病,不仅导致患者的认知、行为、生活能力的全面障碍,严重影响生活质量,也为家庭和社会带来沉重的负担。迄今为止,AD一直缺乏有效的治疗方法。1999年出现的免疫治疗为AD病人带来了希望,本文综述了AD免疫治疗的方法,机制和不同阶段的认识,展望了免疫治疗的进一步发展。     

阿尔茨海默病的免疫治疗

阿尔茨海默病(Alzheimerdisease,AD)是最常见的痴呆性疾病,目前使用的药物治疗效果欠佳,免疫治疗为该病的治疗带来新的希望。主动免疫治疗虽在动物模型取得良好效果,但有少数AD病人诱发了脑膜脑炎。被动免疫治疗在动物模型和AD病人的效果都是令人鼓舞的,但仍需继续观察是否有副作用,并面临抗体选择等诸多问题。现就以上几个方面的研究进展作一综述。     

T淋巴细胞与阿尔茨海默病北大核心CSCD

阿尔茨海默病(AD)是导致痴呆的最常见原因,脑内淀粉样斑块(Aβ)异常沉积是其主要病理特征。T淋巴细胞作为免疫系统的重要组成,在细胞免疫与免疫调节中发挥主导作用。研究表明,AD发生时部分 T淋巴细胞亚群被激活并浸润进入脑内,同时外周免疫系统与外周血中各 T淋巴细胞亚群数量与功能也发生改变。本文主要对 CD3^(+)、CD4^(+)及 CD8^(+)T淋巴细胞,Treg 和各辅助性 T 淋巴细胞亚群在 AD 发生时数量与功能的改变及其潜在作用进行探讨,由于 T 淋巴细胞亚群分群复杂,同时不同研究中 AD 患者处于疾病发生发展的不同阶段,所以文献中具体研究结果可能有所差别,甚至相反。本课题组对现有文献中不同 T 淋巴细胞亚群与 AD 发生发展关系进行总结与探讨,认为 T 淋巴细胞亚群与 AD 的系统研究将为 AD 免疫治疗带来新的曙光。     

揭秘阿尔茨海默病免疫治疗失败的原因

免疫疗法是目前最有希望治疗阿尔茨海默病(Alzheimer’s disease,AD)的策略之一。然而,基于该疗法的抗体药物开发却在临床试验中屡屡失败。过程工程所刘瑞田研究员团队经过多年研究,发现AD抗体药物介导神经突触过度丢失是导致免疫治疗失败的原因,并提出了无效应片段(Fc段)或无效应功能的β淀粉样蛋白(Aβ)抗体具有较好的AD治疗前景这一新策略。     

阿尔茨海默病的免疫治疗研究新进展

阿尔茨海默病（AD）是痴呆最常见的原因。根据淀粉样蛋白级联假说,AD的疫苗治疗成为该病的治疗方法。虽然AD的主动免疫治疗的Ⅱ期临床试验由于一些病人出现了脑膜脑炎而停止,但被治疗病人的临床和病理研究都表明疫苗治疗是有效的。为了避免AB疫苗诱发的脑膜脑炎,研究者试偿了各种各样的方法,其中包括发展短的免疫原、使用新的佐剂、改变给药途径、研制DNA非病毒载体的疫苗和应用催化性抗体。一些在转基因小鼠上的实验研究表明,上述的方法是AD的安全有效的治疗方法。     

Alzheimer患者血清中抗Aβ42自身抗体的纯化及鉴定

目的:纯化并鉴定阿尔茨海默病(AD)患者血清中抗Aβ2自身抗体.方法:选择AD患者做为研究对象,采集血清标本,测定抗体含量,用饱和硫酸铵沉淀血清得到IgG粗品,Aβ42免疫亲和柱层析对粗品IgG进一步分离纯化,采用PAGE电泳和Western blot方法鉴定IgG纯度和免疫活性.结果:用CNBr活化Sephrose 4B柱层析纯化出较高纯度的抗Aβ42自身抗体,纯度可达到90%.结论:CNBr活化Sephrose4B层析柱可有效地从人血清中纯化出较高纯度的抗Aβ42自身抗体,便于对自身抗体进一步研究,为AD的免疫治疗提供更多的信息.     

靶向肝细胞癌的T细胞免疫治疗研究现状

恶性肿瘤严重威胁人类的健康,肿瘤免疫治疗是继手术治疗和放化疗之后第四大治疗方法。目前对于肝细胞癌的免疫治疗尚无十分有效的方法。基因修饰T细胞免疫治疗在血液肿瘤中取得突破性进展,研究者尝试通过T细胞免疫治疗方法突破实体肿瘤的治疗效果。当前针对肝细胞癌免疫治疗的研究十分有限,现就靶向原发性肝癌T细胞免疫治疗的前沿研究现状做一综述。     

肺癌的免疫治疗

肺癌的免疫治疗是当前研究的重要课题之一。在肺癌的治疗计划中对免疫治疗的作用及其效果人们寄予很大的希望。按照患者的病期、病态,适当地并用以往的治疗方法,已发现免疫治疗有明显的效果。本文对肺癌免疫治疗的一些重要方面讨论如下:适应症:肺癌的免疫治疗作为以往治疗方法的辅助治疗而被试用。对可能手术的病     

Midlife predictors of Alzheimer's disease

Factors contributing to increased risk for Alzheimer's disease (AD) include age, sex, genes, and family history of AD. Several risk factors for AD are endogenous; however, accumulating evidence implicates modifiable risk factors in the pathogenesis of AD. Although the continued task of identifying new genes will be critical to learning more about the disease, several research findings suggest that potentially alterable environmental factors influence genetic contributions, providing targets for disease prevention and treatment. Here, we review midlife risk factors for AD, and address the potential for therapeutic intervention in midlife.     

Somatic and germline mosaicism in sporadic early-onset Alzheimer's disease

Alzheimer's disease (AD) is the commonest neurodegenerative disease worldwide. Rare familial cases may be caused by mutations in one of three genes-amyloid precursor protein, presenilin-1 and presenilin-2; however, the molecular basis of >99% of AD cases is unknown. Somatic mutation has been considered to be a mechanism that may account for a proportion of sporadic cases of AD, but to date there has been no evidence for this. We now report a sporadic early-onset patient with AD, and show that this individual is a somatic mosaic for a mutation in the presenilin-1 gene, suggesting a novel molecular mechanism for AD. Quantification of the mosaicism demonstrated the degree of mosaicism at 8% in peripheral lymphocytes and 14% in cerebral cortex in the index patient; a clear gene dosage effect on age of presentation and clinical phenotypic presentation is demonstrated. This finding has important implications for the aetiology of sporadic AD, and for other apparently sporadic neurodegenerative diseases such as Parkinson's disease, motor neuron disease and Creutzfeldt-Jakob disease.     

Prevention trials in Alzheimer's disease: an EU-US task force report

Despite enormous financial and scientific efforts, still no approved disease-modifying therapies exist for Alzheimer's disease (AD). During the last decade all Phase III clinical trials on disease modifiers in AD have failed. The dementia stage of AD being probably too late in order to allow for successful disease modification has been identified as a possible culprit that could explain the failure of so many clinical trials. In parallel, a major development in the diagnostic research field of AD was achieved by the recent proposal of new diagnostic criteria for AD, which also specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD, thus extending the traditional definition of disease to very early stages that may be a more feasible target for various disease modifying therapeutic interventions. This ongoing paradigm shift in AD definition and diagnosis represents a fundamental basis for redefinition of interventional trials in AD, allowing to specifically focus on preventative measures during very early pathophysiologically confirmed stages of disease. This consensus paper reflects the outcome from a European Union and North American Task Force meeting comprised of experts from academia, industry, private foundations, and regulatory agencies that was convened in Toulouse, France on November 5, 2010 and that focused on prevention trials in AD. This position paper thoroughly analyzes prerequisites for successful preventative trials in AD and concludes with concrete recommendations on biomarkers, statistical tools and other variables important for improved study designs suitable for preventative as well as for early therapeutic interventional trials in AD.     

Gender-specific association of the angiotensin converting enzyme gene with Alzheimer's disease

Epidemiological studies have demonstrated that risk factors for vascular disease are also risk factors for Alzheimer's disease (AD). The gene for the angiotensin converting enzyme (ACE) has recently been reported to be associated with risk for AD. We have investigated the possibility of such an association in 98 clinic-based and 73 community-based AD cases versus 175 community-based controls and find a gender-specific association of ACE genotype with AD in the female clinic population. These data suggest that gender may interact with genetic factors to influence risk for AD. Gender-specific risk for AD has been previously reported, and a biological rationale for involvement of ACE in the AD process is supported by studies exploring the relationship between AD and vascular risk factors such as hypertension. However, the results may also be a consequence of the known anomalies that arise in genetic association studies as a consequence of sample selection.     

Prevention trials in Alzheimer's disease: An EU-US task force report

Despite enormous financial and scientific efforts, still no approved disease-modifying therapies exist for Alzheimer's disease (AD). During the last decade all Phase III clinical trials on disease modifiers in AD have failed. The dementia stage of AD being probably too late in order to allow for successful disease modification has been identified as a possible culprit that could explain the failure of so many clinical trials. In parallel, a major development in the diagnostic research field of AD was achieved by the recent proposal of new diagnostic criteria for AD, which also specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD, thus extending the traditional definition of disease to very early stages that may be a more feasible target for various disease modifying therapeutic interventions. This ongoing paradigm shift in AD definition and diagnosis represents a fundamental basis for redefinition of interventional trials in AD, allowing to specifically focus on preventative measures during very early pathophysiologically confirmed stages of disease. This consensus paper reflects the outcome from a European Union and North American Task Force meeting comprised of experts from academia, industry, private foundations, and regulatory agencies that was convened in Toulouse, France on November 5, 2010 and that focused on prevention trials in AD. This position paper thoroughly analyzes prerequisites for successful preventative trials in AD and concludes with concrete recommendations on biomarkers, statistical tools and other variables important for improved study designs suitable for preventative as well as for early therapeutic interventional trials in AD.     

Alzheimer's disease risk genes and the age-at-onset phenotype

Despite the recent identification of several novel risk genes for Alzheimer's disease (AD), little is known about their influence on the age at onset (AAO) of AD. The AAO is a phenotype with a heritable component distinct from disease risk and may be a useful trait to study in the context of developing interventions for delaying the onset of AD. We studied the influence of 10 recently identified AD risk genes and APOE in relation to AAO in a large cohort of AD patients (N = 2569). We find that the novel AD risk gene, PICALM, exerts a small effect on the AAO of AD with earlier disease onset in risk allele carriers. In addition, we confirmed the previously reported association between the APOE ε4 allele and earlier disease onset. None of the other AD risk genes influenced AAO of AD. Our results suggest that besides APOE, other genes associated with AD risk do not exert large effects on the AAO phenotype of AD.     

Neurovascular dysfunction,inflammation and endothelial activation: Implications for the pathogenesis of Alzheimer's disease

Alzheimer's disease (AD) is an age-related disorder characterized by progressive cognitive decline and dementia. Alzheimer's disease is an increasingly prevalent disease with 5.3 million people in the United States currently affected. This number is a 10 percent increase from previous estimates and is projected to sharply increase to 8 million by 2030; it is the sixth-leading cause of death. In the United States the direct and indirect costs of Alzheimer's and other dementias to Medicare, Medicaid and businesses amount to more than $172 billion each year. Despite intense research efforts, effective disease-modifying therapies for this devastating disease remain elusive. At present, the few agents that are FDA-approved for the treatment of AD have demonstrated only modest effects in modifying clinical symptoms for relatively short periods and none has shown a clear effect on disease progression. New therapeutic approaches are desperately needed. Although the idea that vascular defects are present in AD and may be important in disease pathogenesis was suggested over 25 years ago, little work has focused on an active role for cerebrovascular mechanisms in the pathogenesis of AD. Nevertheless, increasing literature supports a vascular-neuronal axis in AD as shared risk factors for both AD and atherosclerotic cardiovascular disease implicate vascular mechanisms in the development and/or progression of AD. Also, chronic inflammation is closely associated with cardiovascular disease, as well as a broad spectrum of neurodegenerative diseases of aging including AD. In this review we summarize data regarding, cardiovascular risk factors and vascular abnormalities, neuro- and vascular-inflammation, and brain endothelial dysfunction in AD. We conclude that the endothelial interface, a highly synthetic bioreactor that produces a large number of soluble factors, is functionally altered in AD and contributes to a noxious CNS milieu by releasing inflammatory and neurotoxic species.     

Relationship between hippocampal volume and CA1 neuron loss in brains of humans with and without Alzheimer's disease

Hippocampal volumetry has been proposed to aid in the early diagnosis of Alzheimer's disease (AD) and to monitor progression of the disease. While this is believed to be as a result of hippocampal neuron loss, this association has not been firmly established and loss of other tissue elements may be responsible for the observed atrophy. We investigated the relationship between neuron loss and hippocampal volume in 11 patients with autopsy-confirmed AD and 11 non-demented age-matched controls. Strong correlations were found between neuron number and both hippocampal volume and brain volume demonstrating that volume and neuron content are related in normal subjects and that the relationship is maintained in AD. In AD, neuron number and volume measures significantly decline with increasing disease duration. These findings support the suggestion that hippocampal atrophy in AD is as a result of neuron loss and confirm the usefulness of volumetry as an indirect measure of neurodegeneration in this disease.     

Platelet Protein Kinase C levels in Alzheimer''s disease

Alzheimer's disease (AD) has been suggested to be a systemic disease, and signal transduction abnormalities have been reported in non-neuronal AD cells. We have previously quantified the protein kinase C (PKC) subtypes in AD and control brains using a two-site enzyme immunoassay (EIA), and have shown that type II PKC levels were significantly reduced in the temporal cortex of AD patients. In this study, we used this EIA to assess the platelet levels of type II PKC in age-matched groups of AD patients and normal controls. The cytosolic level of type II PKC was significantly higher in AD platelets than in control platelets but was unchanged in the membranous fraction. Platelet proteins showed no differences between the AD and control groups. Therefore, the type II PKC content of the cytosolic fraction was increased in AD platelets. These results suggest that type II PKC may be altered in both the brain and platelets of AD patients and support the hypothesis that AD is a systemic disease.     

Twin studies of Alzheimer's disease: An approach to etiology and prevention

Epidemiologic studies of environmental factors associated with risk of Alzheimer's disease (AD) have produced inconsistent and disappointing results. By contrast, family/genetic studies and case control investigations suggest that genetic causes of AD are important. The investigation of such genetic causes remains an important aim in all forms of AD including typical, late-onset disease where linkage work is impractical. But the public health burden of AD creates an especially urgent need to identify environment risk factors, if these exist, since they will more likely be susceptible to intervention. Such environmental factors may interact with genetic susceptibility to accelerate or retard disease expression, and environmental interventions that delay onset may constitute an important strategy for prevention. All these issues may be addressed by twin studies of AD, but the few such studies to date have been limited by small samples and other methodologic difficulties. This paper reviews the rationale for twin studies of AD, and describes briefly the work in this area to date. It also discusses a number of suggestions for methodologic improvements. We conclude that the time is ripe for twin studies of AD, and that such work holds considerable potential for the investigation of etiology and, possibly, for the identification of strategies for prevention.