Boche Delphine, Nicoll James A R, Weller Roy O
Division of Clinical Neurosciences, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, SO16 6YD, UK.
Curr Opin Neurol. 2005 Dec;18(6):720-5. doi: 10.1097/01.wco.0000191513.60368.a7.
The aim of this article is to review the role of immunotherapy in the removal of proteins which accumulate abnormally in neurodegenerative disorders associated with dementia, in particular amyloid-beta accumulation in Alzheimer's disease.
In both transgenic mouse models and in two trials of amyloid-beta immunotherapy for human Alzheimer's disease, active immunization with amyloid-beta 1-42 results in the removal of amyloid-beta plaques from the cerebral cortex associated with, in the mouse models, improvement in cognitive function. Cerebral amyloid angiopathy and neurofibrillary tangles persist, however, and there is also concern about T lymphocyte immune reactions in the meninges in the human cases. Active immunization schedules are being developed to minimize T lymphocyte reactions and to maximize antibody production and passive immunization protocols are being devised. Immunotherapy for removal of the proteins which accumulate in other neurodegenerative disorders associated with dementia such as prion proteins and alpha-synuclein are in the early stages of development.
Dementias in the elderly are an increasing medical, social and economic problem and current treatments are only effective. In the majority of dementias, proteins accumulate within cells and in the extracellular compartments of the brain. In the most common dementia, Alzheimer's disease, amyloid-beta accumulates as plaques in the extracellular space of the grey matter and in artery walls as cerebral amyloid angiopathy and tau protein accumulates as neurofibrillary tangles within neurons.
本文旨在综述免疫疗法在清除与痴呆相关的神经退行性疾病中异常蓄积的蛋白质方面的作用，尤其是阿尔茨海默病中β淀粉样蛋白的蓄积。
在转基因小鼠模型以及两项针对人类阿尔茨海默病的β淀粉样蛋白免疫疗法试验中，用β淀粉样蛋白1-42进行主动免疫可导致大脑皮质中β淀粉样蛋白斑块的清除，在小鼠模型中这与认知功能的改善相关。然而，脑淀粉样血管病和神经原纤维缠结依然存在，并且在人类病例中还存在对脑膜中T淋巴细胞免疫反应的担忧。正在制定主动免疫方案以尽量减少T淋巴细胞反应并最大化抗体产生，同时也在设计被动免疫方案。针对清除在其他与痴呆相关的神经退行性疾病（如朊蛋白和α-突触核蛋白）中蓄积的蛋白质的免疫疗法正处于研发早期阶段。
老年人的痴呆是一个日益严重的医学、社会和经济问题，目前的治疗方法效果有限。在大多数痴呆中，蛋白质在细胞内和大脑的细胞外区室中蓄积。在最常见的痴呆即阿尔茨海默病中，β淀粉样蛋白以斑块形式蓄积在灰质的细胞外空间以及动脉壁中形成脑淀粉样血管病，而tau蛋白则以神经原纤维缠结的形式蓄积在神经元内。
