Aβ中枢及外周清除机制

β淀粉样蛋白(amyloid-βpeptide,Aβ)沉积是阿尔兹海默病(Alzheimer's disease,AD)的病理特征之一。Aβ在体内的清除途径包括:蛋白酶的降解作用、细胞的清除作用、血脑屏障的转运作用、脑脊液和组织间液淋巴引流作用和外周细胞及组织的清除作用。结合最新进展,本文综述了Aβ在中枢和外周的清除机制。     

综述:中性内肽酶在阿尔茨海默病发病机制中的作用

β-淀粉样蛋白(β amyloid,Aβ)在海马区的沉积是阿尔茨海默病(Alzheimer′s disease,AD)发病的典型表现,清除或降低Aβ含量是治疗AD的目标之一．较之Aβ生成的增多,体内降解Aβ能力的下降在AD发病过程中显得更为重要．尽管Aβ在体内可以通过运输到血液和脑脊液途径来清除,但大部分Aβ被中性内肽酶(neprilysin,NEP)为代表的一类蛋白酶降解为小分子后从体内清除．老年人、轻度认知障碍期(MCI)和AD患者的NEP活性显著下降,且NEP活性下降与脑内Aβ升高及AD患者认知功能损伤相关．NEP有可能成为AD治疗的潜在药物靶点,针对轻度认知障碍前期(pre-MCI)和MCI,提高NEP的活性,促进Aβ的降解,有可能延缓AD的发生和发展．     

阿尔茨海默病免疫治疗的临床研究进展

阿尔茨海默病免疫治疗以淀粉样蛋白Aβ或tau蛋白为治疗靶点。通过疫苗刺激产生靶标抗体的主动免疫或直接给予抗体的被动免疫,可减轻AD病理改变,有望延缓或阻止AD病程进展。动物研究显示了广阔的治疗前景,临床免疫治疗的部分药物已完成III期试验,但未达到预期效果。综述近年来免疫治疗AD的临床研究进展。     

综述:靶向淀粉样蛋白的阿尔茨海默病药物研究进展

淀粉样蛋白级联假说是阐释阿尔茨海默病(Alzheimer's disease,AD)发病机制的主要学说之一,即脑内过量的β-淀粉样蛋白(β-amyloid,Aβ)是促发AD的核心因素．因此,靶向Aβ形成、聚集和清除等关键环节的药物开发是目前药物研究的热点．但近年来AD新药临床试验屡屡失败,至今尚未得到一种切实有效的治疗药物．淀粉样蛋白级联假说的局限性和痴呆期患者疾病进程的难以逆转,可能是临床试验反复失败的两个主要原因．借助AD早期诊断技术的发展,将药物干预的时间窗口前移,重视痴呆前期病理机制与治疗的研究,可能是研制延缓AD发生和发展有效药物的新途径．     

运动激活AMPK减少海马Aβ沉积的可能机制

淀粉样蛋白(β-amyloid,Aβ)沉积形成的老年斑是阿尔茨海默病(Alzheimer’s disease,AD)最主要的病理原因之一,其海马内的异常沉积可诱导AD的发病,这与AD动物海马内腺苷酸活化蛋白激酶(AMPK)活性的降低有关。研究发现,适宜的体育运动能够抑制AD动物海马内Aβ的沉积,但具体机制尚不明确。现综述了近期的研究成果,推测适宜的体育运动可以通过消耗ATP,使AMP水平升高,AMP可激活海马内AMPK,激活了的AMPK可通过上调α-分泌酶表达和下调β-分泌酶表达来减少Aβ的生成,从而起到了预防和缓解AD的作用。     

要文聚焦:载脂蛋白E促进β-淀粉样蛋白的清除

β淀粉样蛋白(Aβ)在海马的沉积是阿尔茨海默病(AD)发病的特征性病理改变,Aβ清除减少是造成其沉积的主要原因。载脂蛋白E4(ApoE4)基因能增加散发性AD的发病危险性,但其发挥作用的详细机制不详。最近在《科学》杂志发表的一篇论文发现,类视黄醇X受体激动剂bexarotene能够迅速激活ApoE,进而促进Aβ的降解,并改善痴呆小鼠的行为缺陷。该研究结果明确了ApoE对Aβ降解的促进作用,并为AD的治疗提出了新的设想。     

β-淀粉样蛋白-血红素复合物和蛋白质酪氨酸硝化及其与阿尔茨海默症的关系

β-淀粉样蛋白(Amyloid-β,Aβ)是阿尔茨海默症(Alzheimer’s disease,AD)病人大脑中淀粉样斑块的主要组成部分。β-淀粉样蛋白级联假说指出,Aβ在脑实质的沉积是最终导致阿尔茨海默症的一个关键步骤。目前的大量研究表明,相对于高度聚集的Aβ,可溶性的Aβ低聚物可能与认知功能障碍的关联性更强。血红素(heme)的代谢在AD患者大脑中发生了改变。近来发现heme可与Aβ结合,形成一个复合物Aβ-heme,该复合物拥有显著高于heme的过氧化物酶活性,具有比heme更强的催化蛋白质酪氨酸硝化的能力。这个结果提示,Aβ-heme可能是联系Aβ与AD中大量蛋白质发生硝化的关键分子。同时,Aβ与heme的结合改变了heme催化蛋白质硝化的位点选择性。这些研究对于阐明Aβ和heme在体内可能的生理作用具有重要意义。     

基于淀粉样蛋白级联假说的阿尔茨海默症防治研究进展

阿尔茨海默症（Alzheimer＇s Disease,AD）是一种中枢神经系统退行性病变,目前发病机制不清。淀粉样蛋白级联假说是有关AD发病机制的主流学说,认为脑内过量产生的β-淀粉样蛋白（β-amyloid peptide,Aβ）是引发AD的主要原因。针对Aβ的生成、聚集、清除及靶向治疗相关的药物开发是目前的研究热点,就淀粉样蛋白级联假说的最新研究进展及AD的预防治疗现状作一综述。     

分子疫苗防治老年性痴呆小鼠模型的研究进展

老年斑是老年性痴呆(Alzheimer's disease, AD)的特征性病理改变,β-淀粉样(β-amyloid,Aβ)是其主要成分.将Aβ作为疫苗对动物进行免疫,有明显抑制转基因小鼠脑内Aβ的沉积,清除原有斑块的作用,从而减少异常Aβ沉积对认知功能的损害.疫苗没有引起针对动物自身抗原的免疫反应,对中枢神经系统的正常功能也没有明显损害.     

凝溶胶蛋白治疗阿尔茨海默症的研究进展

阿尔茨海默症(Alzheimer’s disease,AD)的病理学特征之一是患者脑内存在以β-淀粉样肽(Aβ)为主要成分的老年斑。大量的实验证据表明,以Aβ为靶目标,清除老年斑有助于提高患者的认知能力,是防治AD的一个重要研究方向。凝溶胶蛋白在细胞骨架结构重排和细胞运动等过程中都发挥重要作用。目前多个小组的研究成果显示,凝溶胶蛋白与AD的发生、发展密切相关。凝溶胶蛋白能够抑制Aβ积聚形成纤维,也能够引发已形成的Aβ纤维发生解聚。更重要的是,凝溶胶蛋白能够清除转基因AD模型小鼠脑内的老年斑和降低Aβ的水平。未来凝溶胶蛋白有可能被应用于AD的预防和治疗。     

Immunotherapy for Alzheimer's disease: will vaccination work?

Active or passive immunization against the beta-amyloid peptide (Abeta) has been proposed as a method for preventing and/or treating Alzheimer's disease (AD). In addition to lowering brain Abeta and amyloid burden in transgenic mouse models of AD, a beneficial effect of immunization on previously characterized memory impairment(s) has also been reported in these mice. Whether these preclinical data will predict efficacy in AD patients remains to be seen. A clinical trial of active immunization (vaccination) was halted, owing to a serious adverse event (meningoencephalitis), raising questions about the safety of this approach. Two recent reports suggest that immunotherapy-based approaches to treating and preventing AD will require careful antigen and antibody selection, to maximize efficacy and minimize serious adverse events. However, given the potential efficacy of this approach, we believe that immunotherapy for AD should not be prematurely abandoned.     

Immunotherapy with beta-amyloid for Alzheimer's disease: a new frontier.

Alzheimer's disease (AD) represents the fourth leading cause of death in the U.S. and the leading cause of dementia in the elderly population. Until recently, there was little hope of finding a way to prevent the underlying brain pathology from progressing toward the inevitable conclusion of the disease. However, new immunotherapeutic approaches have been described that are based on vaccination with the beta-amyloid 1-42 peptide (Abeta). The encouraging efficacy and safety of Abeta immunization in reducing neuropathology in animal models of AD has opened up new therapeutic possibilities for patients. Immunization with Abeta is aimed at reducing the Abeta-associated pathology of AD. It is hypothesized that this approach will also reduce the cascade of downstream events leading to neuronal cell loss and, ultimately, dementia. The ensuing articles in this issue describe various aspects of the Abeta immunization strategy and their potential relevance to AD treatment.     

Amelioration of amyloid load by anti-Abeta single-chain antibody in Alzheimer mouse model

Parenteral immunization of transgenic mouse models of Alzheimer disease (AD) with synthetic amyloid beta-peptide (Abeta) prevented or reduced Abeta deposits and attenuated their memory and learning deficits. A clinical trial of immunization with synthetic Abeta, however, was halted due to brain inflammation, presumably induced by a toxic Abeta, T-cell- and/or Fc-mediated immune response. Another issue relating to such immunizations is that some AD patients may not be able to raise an adequate immune response to Abeta vaccination due to immunological tolerance or age-associated decline. Because peripheral administration of antibodies against Abeta also induced clearance of amyloid plaques in the model mice, injection of humanized Abeta antibodies has been proposed as a possible therapy for AD. By screening a human single-chain antibody (scFv) library for Abeta immunoreactivity, we have isolated a scFv that specifically reacts with oligomeric Abeta as well as amyloid plaques in the brain. The scFv inhibited Abeta amyloid fibril formation and Abeta-mediated cytotoxicity in vitro. We have tested the efficacy of the human scFv in a mouse model of AD (Tg2576 mice). Relative to control mice, injections of the scFv into the brain of Tg2576 mice reduced Abeta deposits. Because scFvs lack the Fc portion of the immunoglobulin molecule, human scFvs against Abeta may be useful to treat AD patients without eliciting brain inflammation.     

The underestimated potential of the immune system in prevention of Alzheimer's disease pathology

Genetic and environmental factors leading to Alzheimer's disease (AD) converge in a pathogenic pathway that leads to the accumulation of mis-folded amyloid peptide (Abeta) in the brain. Removal of Abeta from the brain has thus been the focus of academic and industrial research in the last decade. The concept of immunization therapy could be proven in animal models mimicking amyloid pathology but a multicenter clinical trial in which AD patients were vaccinated with aggregated Abeta has resulted in somewhat unanticipated and partially conflicting results. The occurrence of meningoencephalitis in 6% of vaccinated individuals forced the discontinuation of the clinical study, preventing the generation of sufficient data for an unequivocal statement about the effectiveness of such a therapy approach. This study, however, clearly showed that vaccination induced the production of antibodies against Abeta in some immunized patients. Moreover, circulating anti-Abeta antibodies are found in healthy humans suggesting a protective role of such physiological antibodies. Nonetheless, the physiological role of the immune system in preventing AD is not fully understood. This article summarizes crucial animal and clinical data underscoring the potential of the immune system for AD treatment.     

Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease

To characterize antibodies produced in humans in response to Abeta42 vaccination, we carried out immunohistochemical examinations of the brains of both transgenic mice and human patients with beta-amyloid pathology. We collected sera from patients with Alzheimer disease who received a primary injection of pre-aggregated Abeta42 followed by one booster injection in a placebo-controlled study. Antibodies in immune sera recognized beta-amyloid plaques, diffuse Abeta deposits and vascular beta-amyloid in brain blood vessels. The antibodies did not cross-react with native full-length beta-amyloid precursor protein or its physiological derivatives, including soluble Abeta42. These findings indicate that vaccination of AD patients with Abeta42 induces antibodies that have a high degree of selectivity for the pathogenic target structures. Whether vaccination to produce antibodies against beta-amyloid will halt the cognitive decline in AD will depend upon clinical assessments over time.     

Behavioral assessment of Alzheimer's transgenic mice following long-term Abeta vaccination: task specificity and correlations between Abeta deposition and spatial memory.

Long-term vaccinations with human beta-amyloid peptide 1-42 (Abeta1-42) have recently been shown to prevent or markedly reduce Abeta deposition in the PDAPP transgenic model of Alzheimer's disease (AD). Using a similar protocol to vaccinate 7.5-month-old APP (Tg2576) and APP+PS1 transgenic mice over an 8-month period, we previously reported modest reductions in brain Abeta deposition at 16 months. In these same mice, Abeta vaccinations had no deleterious behavioral effects and, in fact, benefited the mice by providing partial protection from age-related deficits in spatial working memory in the radial arm water maze task (RAWM) at 15.5 months. By contrast, control-vaccinated transgenic mice exhibited impaired performance throughout the entire RAWM test period at 15.5 months. The present study expands on our initial report by presenting additional behavioral results following long-term Abeta vaccination, as well as correlational analyses between cognitive performance and Abeta deposition in vaccinated animals. We report that 8 months of Abeta vaccinations did not reverse an early-onset balance beam impairment in transgenic mice. Additionally, in Y-maze testing at 16 months, all mice showed comparable spontaneous alternation irrespective of genotype or vaccination status. Strong correlations were nonetheless present between RAWM performance and extent of "compact" Abeta deposition in both the hippocampus and the frontal cortex of vaccinated APP+PS1 mice. Our results suggest that the behavioral protection of long-term Abeta vaccinations is task specific, with preservation of hippocampal-associated working memory tasks most likely to occur. In view of the early short-term memory deficits exhibited by AD patients, Abeta vaccination of presymptomatic AD patients could be an effective therapeutic to protect against such cognitive impairments.     

Reduced serum level of antibodies against amyloid beta peptide is associated with aging in Tg2576 mice

Both active and passive immunization to eliminate amyloid plaques from the brain of patients with Alzheimer's disease (AD) have confirmed that amyloid beta (Abeta) vaccination does not only result in clearance of Abeta plaques but improves behavioral-cognitive deficits in animal models of AD. In the present study, the levels of naturally occurring serum antibodies against Abeta were measured in Tg2576 mice at various ages using ELISA to determine the relationship between aging and the level of anti-Abeta autoantibody. The level of anti-Abeta antibody fell significantly at the age of 9 months, at the age when amyloid plaques started to appear in the brain of Tg2576 mice, and was persistently low thereafter. However, serum immunoglobulin (Ig) level was elevated in older transgenic mice compared with younger transgenic mice suggesting that the reduced level of anti-Abeta autoantibody was not merely due to deterioration of the immune response in aged Tg2576 mice.     

I32E and V36K double mutation in beta2-sheet abrogates amyloid beta peptide toxicity

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, wherein, the accumulation of amyloid beta (Abeta) peptide as cytotoxic oligomers leads to neuropathologic changes. Transgenic mice with brain Abeta plaques immunized with aggregated Abeta have reduced amyloid burden and improved cognitive functions. However, such active immunization in humans led to a small but significant occurrence of meningoencephalitis in 6% AD volunteers due to Abeta induced toxicity. In an attempt to develop safer alternative vaccines, the design of a highly soluble peptide homologous to Abeta (Abeta-EK), that has a reduced amyloidogenic potential while maintaining the major immunogenic epitopes of Abeta is reported. More importantly, this homologue has been shown to be non-toxic, as this peptide failed to exert any observable effect on erythrocytes. The results of the present study suggests that immunization with non-toxic Abeta derivative may offer a safer therapeutic approach to AD, instead of using toxic Abeta fibrils.     

Nasal vaccination with beta-amyloid peptide for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a severe neurodegenerative disease for which there is currently no effective prevention or treatment. The prediction that the number of U.S. patients with AD will triple to approximately 14 million over the next 50 years underscores the urgent need to explore novel therapeutic strategies for AD. The beta-amyloid protein (Abeta) accumulation and accompanying inflammation appear to play key roles in initiating the neuronal degeneration that underlies the signs and symptoms of AD. Interventions geared toward reducing Abeta accumulation and inflammatory responses should delay or prevent the onset of the clinical disease. Recently, several research groups, including ours, have shown that vaccination with Abeta results in a significant lowering of the Abeta burden in the brains of APP transgenic mice and, in some studies, improvement in their cognitive deficits. Our study described a novel approach, namely mucosal (intranasal) Abeta vaccination. Precisely how Abeta vaccination chronically lowers Abeta levels and reduces Abeta-associated pathology remains unclear. Here, we provide an overview of these studies, with particular emphasis on our work with intranasal Abeta vaccination. Examples of other intranasal vaccines and mucosal adjuvants are presented. Taken together, these data have implications for the future development of an intranasal Abeta vaccine for humans.     

Nasal inoculation of an adenovirus vector encoding 11 tandem repeats of Abeta1-6 upregulates IL-10 expression and reduces amyloid load in a Mo/Hu APPswe PS1dE9 mouse model of Alzheimer's disease

BACKGROUND: One of the pathological hallmarks of Alzheimer's disease (AD) is deposits of amyloid beta-peptide (Abeta) in neuritic plaques and cerebral vessels. Immunization of AD mouse models with Abeta reduces Abeta deposits and improves memory and learning deficits. Because recent clinical trials of immunization with Abeta were halted due to brain inflammation that was presumably induced by a T-cell-mediated autoimmune response, vaccination modalities that elicit predominantly humoral immune responses are currently being developed. METHODS: We have nasally immunized a young AD mouse model with an adenovirus vector encoding 11 tandem repeats of Abeta1-6 fused to the receptor-binding domain (Ia) of Pseudomonas exotoxin A (PEDI), AdPEDI-(Abeta1-6)(11), in order to evaluate the efficacy of the vector in preventing Abeta deposits in the brain. We also have investigated immune responses of mice to AdPEDI-(Abeta1-6)(11). RESULTS: Nasal immunization of an AD mouse model with AdPEDI-(Abeta1-6)(11) elicited a predominant IgG1 response and reduced Abeta load in the brain. The plasma IL-10 level in the AD mouse model was upregulated after immunization and, upon the stimulation with PEDI-(Abeta1-6)(11), marked IL-10 responses were found in splenic CD4(+) T cells from C57BL/6 mice that had been immunized with AdPEDI-(Abeta1-6)(11). CONCLUSIONS: These results suggest that the induction of Th2-biased responses with AdPEDI-(Abeta1-6)(11) in mice is mediated in part through the upregulation of IL-10, which inhibits activation of dendritic cells that dictate the induction of Th1 cells.