The Emerging Role of Innate Immunity in Alzheimer's Disease.
The Emerging Role of Innate Immunity in Alzheimer's Disease.
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先天免疫在阿尔茨海默病中的新作用。
DOI：
10.1038/npp.2016.226
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Moir,RobertD
中科院分区：
文献类型：
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作者：
VijayaKumar,DeepakKumar;Moir,RobertD
淀粉样蛋白级联假说是阿尔茨海默病（AD）病理的主要模型，并指导了20多年来的阿尔茨海默病药物开发策略。该假说认为，β-淀粉样蛋白（a β）寡聚化导致的β-淀粉样蛋白斑块在大脑中过度积累，驱动了神经退行性级联反应，包括tau蛋白产生神经原纤维缠结（nft）。nft是阿尔茨海默病的标志性病理。大量的遗传和生化数据支持Aβ纤化途径在AD病理中的首要地位。Choi等人（2014）的一项具有里程碑意义的研究最近也证实，β-淀粉样蛋白的产生导致了再现AD病理的新型3D人类神经元细胞培养模型中的nft （Choi等人，2014）。然而，在过去的二十年中，Aβ和β-淀粉样蛋白在淀粉样蛋白级联模型中所起的作用发生了显著的变化。最初，不溶性β-淀粉样斑块被视为驱动神经变性。现在认为介导AD病理的关键物质是在Aβ纤维化过程中产生的可溶性寡聚体中间体。如果最近发现的Aβ的抗菌功能，以及AD与先天免疫基因之间的联系（Bertram和Tanzi， 2012）得到证实，不久的将来可能会对淀粉样蛋白级联模型进行进一步的实质性调整。重要的是，阿尔茨海默病淀粉样变的新先天免疫模型可能对正在进行和未来的阿尔茨海默病治疗工作有相当大的兴趣（图1）。在AD淀粉样蛋白形成的主流模型中，Aβ寡聚和产生β-淀粉样蛋白的倾向被认为是一种内在异常和完全病理的活动。然而，最近的研究结果表明，Aβ寡聚化可能有助于保护大脑免受感染。Aβ显示出对人类病原体有效的体外杀微生物活性，与抗菌肽的特性一致（Soscia等，2010）。Aβ的表达
The amyloid cascade hypothesis is the dominant model for Alzheimer's disease (AD) pathology and has guided AD drug development strategies for over two decades. The hypothesis states that excessive cerebral accumulation of β-amyloid plaques from oligomerization of amyloid-β protein (Aβ) drives a neurodegenerative cascade, including generation of neurofibrillary tangles (NFTs) from tau protein. NFTs are a hallmark pathology for AD. Overwhelming genetic and biochemical data support the primacy of Aβ fibrillization pathways in AD pathology. A landmark study by Choi et al (2014) also recently confirmed that β-amyloid generation leads to NFTs in novel 3D human neuronal cell culture models that recapitulate AD pathologies (Choi et al, 2014). However, the roles played by Aβ and β-amyloid in the amyloid cascade model has shifted markedly during the last two decades. Initially, insoluble β-amyloid plaques were viewed as driving neurodegeneration. The key species mediating AD pathology are now thought to be soluble oligomeric intermediates generated during Aβ fibrillization. The near future may see further substantial adjustments to the amyloid cascade model if recent findings of an antimicrobial function for Aβ, and links between AD and innate immune genes (Bertram and Tanzi, 2012) are confirmed. Importantly, new innate immune models of AD amyloidosis are likely to be of considerable interest for ongoing and future AD therapeutic efforts (Figure 1).In prevailing models of AD amyloidogenesis, Aβ's propensity to oligomerize and generate β-amyloid is viewed as an intrinsically abnormal and exclusively pathological activity. However, recent findings suggest Aβ oligomerization may help protect the brain from infection. Aβ shows potent in vitro microbicidal activities against human pathogens, consistent with identity as an antimicrobial peptide (Soscia et al, 2010). Aβ expression also