Autoreactive-Aβ antibodies promote APP β-secretase processing.
Autoreactive-Aβ antibodies promote APP β-secretase processing.
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DOI：
10.1111/j.1471-4159.2011.07629.x
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发表时间：
2012-03
影响因子：
4.7
通讯作者：
Tan J
中科院分区：
文献类型：
--
作者：
Deng J;Hou H;Giunta B;Mori T;Wang YJ;Fernandez F;Weggen S;Araki W;Obregon D;Tan J
先前对阿尔茨海默病（AD）患者的几项研究表明，可以产生针对淀粉样蛋白-β (Aβ)物种的天然自身抗体。虽然许多研究都集中在AD和衰老中抗a β相关蛋白的自身抗体的相对浓度或结合亲和力上，但关于其功能特性的数据有限。一般认为这些抗体的作用是帮助清除Aβ。然而，由于与Aβ结合的抗体通常也与亲本淀粉样前体蛋白（APP）结合，我们推断某些Aβ靶向自身抗体可能与APP结合，从而改变其构象和加工。本研究首次发现，从阿尔茨海默病患者而非健康人体内分离的a β反应性自身抗体可促进培养细胞中β分泌酶的活性。此外，利用针对Aβ不同区域的单克隆抗体，我们发现针对n端区域，特别是Aβ1 - 17产生的抗体，通过β分泌酶激活，剂量依赖性地促进了APP的淀粉样变性加工。因此，某些自身抗体驱动Aβ生成的特性可能在散发性AD的发展中具有重要的病因学意义。此外，未来的被动或主动抗Aβ免疫疗法必须考虑抗体针对Aβ的n端产生的潜在脱靶效应，因为与APP相应区域的共结合实际上可能会增强Aβ的生成。
Several prior investigations of Alzheimer's disease (AD) patients have indicated naturally-occurring autoantibodies against amyloid-β (Aβ) species are produced. While many studies have focused on the relative concentrations or binding affinities of autoantibodies against Aβ-related proteins in AD and aging, data regarding their functional properties are limited. It is generally believed that these antibodies act to aid in clearance of Aβ. However, as antibodies which bind to Aβ also typically bind to the parent amyloid precursor protein (APP), we reasoned that certain Aβ-targeting autoantibodies may bind to APP thereby altering its conformation and processing. Here we show for the first time, that naturally occurring Aβ-reactive autoantibodies isolated from AD patients, but not from healthy controls, promote β-secretase activity in cultured cells. Further, using monoclonal antibodies to various regions of Aβ, we found that antibodies generated against the N-terminal region, especially Aβ1–17, dose dependently promoted amyloidogenic processing of APP via β-secretase activation. Thus, this property of certain autoantibodies in driving Aβ generation could be of etiological importance in the development of sporadic forms of AD. Furthermore, future passive or active anti-Aβ immunotherapies must consider potential off-target effects resulting from antibodies targeting the N-terminus of Aβ, as co-binding to the corresponding region of APP may actually enhance Aβ generation.
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DOI：
10.1073/pnas.151261398
发表时间：
2001-07-17
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
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