Hawkes Cheryl A, McLaurin Joanne
Center for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
Expert Rev Neurother. 2007 Nov;7(11):1535-48. doi: 10.1586/14737175.7.11.1535.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized pathologically by the deposition of beta-amyloid (A beta)-containing extracellular neuritic plaques, intracellular neurofibrillary tangles and neuronal loss. Much evidence supports the hypothesis that A beta peptide aggregation contributes to AD pathogenesis, however, currently approved therapeutic treatments do nothing to stop or reverse A beta deposition. The success of active and passive anti-A beta immunotherapies in both preventing and clearing parenchymal amyloid in transgenic mouse models led to the initiation of an active anti-A beta vaccination (AN1792) trial in human patients with mild-to-moderate AD, but was prematurely halted when 6% of inoculated patients developed aseptic meningoencephalitis. Autopsy results from the brains of four individuals treated with AN1792 revealed decreased plaque burden in select brain areas, as well as T-cell lymphocytes in three of the patients. Furthermore, antibody responders showed some improvement in memory task measures. These findings indicated that anti-A beta therapy might still be a viable option for the treatment of AD, if potentially harmful proinflammatory processes can be avoided. Over the past 6 years, this target has led to the development of novel experimental immunization strategies, including selective A beta epitope targeting, antibody and adjuvant modifications, as well as alternative routes and mechanisms of vaccine delivery, to generate anti-A beta antibodies that selectively target and remove specific A beta species without evoking autoimmunity. Results from the passive vaccination AD clinical trials that are currently underway will provide invaluable information about both the effectiveness of newly improved anti-A beta vaccines in clinical treatment, as well as the role of the A beta peptide in the pathogenesis of the disease.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其病理特征为含有β-淀粉样蛋白（Aβ）的细胞外神经炎性斑块沉积、细胞内神经原纤维缠结和神经元丢失。许多证据支持Aβ肽聚集促成AD发病机制的假说，然而，目前获批的治疗方法无法阻止或逆转Aβ沉积。主动和被动抗Aβ免疫疗法在转基因小鼠模型中预防和清除实质淀粉样蛋白方面取得的成功，促使针对轻度至中度AD患者开展了一项主动抗Aβ疫苗接种（AN1792）试验，但在6%的接种患者发生无菌性脑膜脑炎后试验提前终止。对四名接受AN1792治疗的个体大脑进行尸检的结果显示，特定脑区的斑块负担减轻，三名患者的大脑中还发现了T细胞淋巴细胞。此外，产生抗体的患者在记忆任务测量方面有一定改善。这些发现表明，如果能够避免潜在有害的促炎过程，抗Aβ疗法可能仍是治疗AD的可行选择。在过去6年中，这一靶点促使人们开发了新的实验性免疫策略，包括选择性靶向Aβ表位、抗体和佐剂修饰，以及疫苗递送的替代途径和机制，以产生能够选择性靶向并清除特定Aβ种类而不引发自身免疫的抗Aβ抗体。目前正在进行的被动疫苗接种AD临床试验结果，将为新改进的抗Aβ疫苗在临床治疗中的有效性以及Aβ肽在疾病发病机制中的作用提供宝贵信息。
