Institute of Applied Biotechnology, Faculty for Biotechnology, Biberach University of Applied Science, Karlstrasse 11, Biberach/Riss, D-88400, Germany.
Immun Ageing. 2013 May 11;10(1):18. doi: 10.1186/1742-4933-10-18.
Alzheimer's disease (AD) is the most common dementia in the industrialized world, with prevalence rates well over 30% in the over 80-years-old population. The dementia causes enormous costs to the social healthcare systems, as well as personal tragedies for the patients, families and caregivers. AD is strongly associated with Amyloid-beta (Aβ) protein aggregation, which results in extracellular plaques in the brain, and according to the amyloid cascade hypothesis appeared to be a promising target for the development of AD therapeutics. Within the past decade convincing data has arisen positioning the soluble prefibrillar Aβ-aggregates as the prime toxic agents in AD. However, different Aβ aggregate species are described but their remarkable metastability hampers the identification of a target species for immunization. Passive immunotherapy with monoclonal antibodies (mAbs) against Aβ is in late clinical development but recently the two most advanced mAbs, Bapineuzumab and Solanezumab, targeting an N-terminal or central epitope, respectively, failed to meet their target of improving or stabilizing cognition and function. Preliminary data from off-label treatment of a small cohort for 3 years with intravenous polyclonal immunoglobulins (IVIG) that appear to target different conformational epitopes indicate a cognitive stabilization. Thus, it might be the more promising strategy reducing the whole spectrum of Aβ-aggregates than to focus on a single aggregate species for immunization.
阿尔茨海默病（AD）是工业化世界中最常见的痴呆症，80 岁以上人群的患病率超过 30%。这种痴呆症给社会医疗保健系统带来了巨大的成本，也给患者、家庭和护理人员带来了个人悲剧。AD 与淀粉样蛋白-β（Aβ）蛋白聚集强烈相关，这导致大脑中出现细胞外斑块，根据淀粉样蛋白级联假说，它似乎是开发 AD 治疗药物的一个有前途的靶点。在过去的十年中，令人信服的数据表明，可溶性原纤维状 Aβ-聚集物是 AD 的主要毒性物质。然而，不同的 Aβ 聚集物种类被描述，但它们显著的亚稳性阻碍了对免疫目标物的鉴定。针对 Aβ 的单克隆抗体（mAbs）的被动免疫疗法处于晚期临床开发阶段，但最近两种最先进的 mAbs，Bapineuzumab 和 Solanezumab，分别针对 N 端或中央表位，未能达到改善或稳定认知和功能的目标。静脉注射多克隆免疫球蛋白（IVIG）对小队列进行为期 3 年的非标签治疗的初步数据表明，针对不同构象表位的 IVIG 似乎具有认知稳定性。因此，与针对免疫接种的单一聚集物种类相比，减少整个 Aβ-聚集物谱可能是更有前途的策略。
