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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Novel approaches for immunotherapeutic intervention in Alzheimer's disease.
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Novel approaches for immunotherapeutic intervention in Alzheimer's disease.

机译：阿尔茨海默氏病免疫治疗干预的新方法。

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摘要

Immunotherapy can attenuate amyloid neuropathology and improve cognitive function in transgenic models of Alzheimer's disease. However, the first clinical trial was halted when 6% of the Alzheimer's patients developed aseptic meningoencephalitis. Postmortem analysis of two cases with meningoencephalitis showed robust glial activation, T-cell infiltration and sporadic clearance of Abeta. Interestingly, transgenic mouse models of Alzheimer's disease failed as predictors of these adverse inflammatory events. However there are now several studies with amyloid precursor protein transgenic mice that have reported an increased risk of microhemorrhages at sites of cerebrovascular amyloid deposits and because approximately 80% of Alzheimer's patient's have cerebrovascular pathology, there is concern regarding clinical trials using passive administration of humanized anti-Abeta antibodies. Although many studies have now been published on immunotherapy in mouse models, the mechanism(s) of antibody-mediated clearance of beta-amyloid from the brain, and the cause of the antibody-induced microhemorrhages remain unclear. In this review, we will discuss the most recent results from the first clinical trial, offer speculation on possible causes for the failure of the trial, review data on antibody-mediated clearance mechanisms, explore the role of complement and inflammation in the clearance of beta-amyloid, and suggest novel strategies for avoiding problems in future clinical trials. The central hypothesis being proposed in this review is that anti-Abeta antibodies delivered directly to the CNS at the sites of amyloid deposits will be far more effective at clearing Abeta and safer than active or passive immunization strategies where the majority of the antibodies are in the periphery.
机译：在阿尔茨海默氏病转基因模型中，免疫疗法可以减弱淀粉样蛋白的神经病理学并改善认知功能。但是，当6％的阿尔茨海默氏病患者发展为无菌性脑膜脑炎时，第一项临床试验就中止了。对2例脑膜脑炎患者进行的事后分析显示，神经胶质激活活跃，T细胞浸润和Abeta偶发清除。有趣的是，阿尔茨海默氏病的转基因小鼠模型未能成功预测这些不良炎症事件。但是，现在有几项关于淀粉样蛋白前体蛋白转基因小鼠的研究表明，在脑血管淀粉样蛋白沉积部位发生微出血的风险增加，并且由于约80％的阿尔茨海默氏病患者患有脑血管病变，因此人们对使用被动给药的人源化抗-Abeta抗体。尽管现在已经发表了许多关于小鼠模型免疫疗法的研究，但是尚不清楚抗体介导的从大脑清除β-淀粉样蛋白的机制以及抗体诱发的微出血的原因。在这篇综述中，我们将讨论第一项临床试验的最新结果，推测试验失败的可能原因，回顾抗体介导的清除机制的数据，探讨补体和炎症在β清除率中的作用-淀粉样蛋白，并提出避免未来临床试验中出现问题的新策略。本综述提出的主要假设是，直接传递至淀粉样蛋白沉积位点中枢神经系统的抗Abeta抗体在清除Abeta方面要比主动或被动免疫策略有效得多，后者的主动或被动免疫策略大多数是在周边。

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