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Immunotherapy for Alzheimer's Disease: Potential Problems and Possible Solutions

机译：阿尔茨海默氏病的免疫疗法：潜在的问题和可能的解决方案

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摘要

The primary component of senile plaques is the β-amyloid peptide (Aβ), and the amyloid cascade hypothesis proposes that this putative neuropathological peptide is a causal factor in the onset and progression of Alzheimer's disease (AD). Many of the strategies currently being investigated as therapies for AD are aimed at reducing the level of Aβ in the brain or blocking the assembly of the peptide into potentially pathological forms. Immunization of APP/Tg mice with fibrillar Aβ, induced anti-Aβ antibodies, which reduced Ab plaque deposition and neuritic dystrophy, astrogliosis in the brains of APP/Tg mice, and diminished learning deficits in these mice. The first clinical trial was halted, however, when 6% of the participants developed some degree of meningoencephalitis. Preliminary analysis of the first clinical trial has produced some encouraging results including a reduction in plaque load and attenuation of cognitive decline in some vaccinated patients. In this review, we discuss the current status of Aβ-immunotherapy and offer our analysis of the probable cause of the failure of the clinical trial. We believe that the development of safe and effective Aβ-immunotherapy requires selection of an antigen that will induce an adequate anti-Aβ antibody response in the absence of potentially adverse self T cell- mediated events.
机译：老年斑的主要成分是β-淀粉样肽（Aβ），淀粉样蛋白级联假设表明，这种假定的神经病理学肽是阿尔茨海默氏病（AD）发病和进展的原因。当前正在研究的许多用于AD疗法的策略旨在降低大脑中Aβ的水平或阻止肽组装成潜在的病理形式。用原纤维Aβ免疫APP / Tg小鼠，诱导产生抗Aβ抗体，从而减少Ab /斑块沉积和神经营养不良，APP / Tg小鼠大脑中的星形胶质变，并减少这些小鼠的学习缺陷。但是，只有6％的参与者患上某种程度的脑膜脑炎时，才停止了第一项临床试验。首次临床试验的初步分析产生了一些令人鼓舞的结果，包括减少了部分接种疫苗的患者的斑块负荷和减轻了认知能力下降。在这篇综述中，我们讨论了Aβ免疫疗法的现状，并提供了对临床试验失败的可能原因的分析。我们认为，开发安全有效的Aβ免疫疗法需要选择一种抗原，该抗原在没有潜在的不良T细胞介导事件的情况下会诱导足够的抗Aβ抗体应答。

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