Deglycosylated anti-amyloid beta antibodies reduce microglial phagocytosis and cytokine production while retaining the capacity to induce amyloid beta sequestration.
Deglycosylated anti-amyloid beta antibodies reduce microglial phagocytosis and cytokine production while retaining the capacity to induce amyloid beta sequestration.
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去糖基化的抗β-淀粉样蛋白抗体可减少小胶质细胞的吞噬作用和细胞因子的产生，同时保留诱导β-淀粉样蛋白隔离的能力。
DOI：
10.1111/j.1460-9568.2007.05852.x
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Matsuoka,Yasuji
中科院分区：
文献类型：
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作者：
Takata,Kazuyuki;Hirata-Fukae,Chiho;Becker,AmandaG;Chishiro,Saori;Gray,AudreyJ;Nishitomi,Kouhei;Franz,AndreasH;Sakaguchi,Gaku;Kato,Akira;Mattson,MarkP;Laferla,FrankM;Aisen,PaulS;Kitamura,Yoshihisa;Matsuoka,Yasuji
淀粉样蛋白β（Abeta）的积累是阿尔茨海默病的病理标志，降低Abeta是一种有前途的治疗方法。完整的抗Abeta抗体通过两种途径减少脑Abeta：增强的小胶质细胞吞噬作用和Abeta从脑转移到外周（Abeta隔离）。虽然对小胶质细胞吞噬作用至关重要的小胶质细胞的激活必然伴随着不期望的神经炎症事件，但隔离的能力似乎与这种作用无关。我们和其他小组已经发现，简单的Abeta结合剂足以通过螯合途径减少脑Abeta。在这项研究中，我们的目的是消除潜在的有害免疫激活抗体，而不影响诱导隔离的能力。免疫球蛋白的聚糖部分主要参与与免疫效应物（包括Fc受体和补体c1 q）的相互作用;去糖基化消除了这些相互作用，同时保持了抗原（Abeta）结合亲和力。在这项研究中，我们研究了去糖基化抗Abeta抗体是否减少小胶质细胞吞噬作用和神经炎症，而不改变诱导Abeta隔离的能力。去糖基化抗体维持Abeta结合亲和力。去糖基化抗体没有增强原代培养的小胶质细胞中的Abeta吞噬作用或细胞因子释放，而完整抗体则显著增强。在无或有Abeta斑块病理的阿尔茨海默氏症转基因小鼠模型中，与完整抗体相比，静脉注射去糖基化抗体升高血浆Abeta水平并诱导Abeta螯合至相似或更高的程度。我们的结论是，去糖基化抗体有效地诱导Abeta隔离，而不引起神经炎症，因此，这些去糖基化抗体可能是最佳的隔离治疗阿尔茨海默氏病。
Accumulation of amyloid beta (Abeta) is a pathological hallmark of Alzheimer's disease, and lowering Abeta is a promising therapeutic approach. Intact anti‐Abeta antibodies reduce brain Abeta through two pathways: enhanced microglial phagocytosis and Abeta transfer from the brain to the periphery (Abeta sequestration). While activation of microglia, which is essential for microglial phagocytosis, is necessarily accompanied by undesired neuroinflammatory events, the capacity for sequestration does not seem to be linked to such effects. We and other groups have found that simple Abeta binding agents are sufficient to reduce brain Abeta through the sequestration pathway. In this study, we aimed to eliminate potentially deleterious immune activation from antibodies without affecting the ability to induce sequestration. The glycan portion of immunoglobulin is critically involved in interactions with immune effectors including the Fc receptor and complement c1q; deglycosylation eliminates these interactions, while antigen (Abeta)‐binding affinity is maintained. In this study, we investigated whether deglycosylated anti‐Abeta antibodies reduce microglial phagocytosis and neuroinflammation without altering the capacity to induce Abeta sequestration. Deglycosylated antibodies maintained Abeta binding affinity. Deglycosylated antibodies did not enhance Abeta phagocytosis or cytokine release in primary cultured microglia, whereas intact antibodies did so significantly. Intravenous injection of deglycosylated antibodies elevated plasma Abeta levels and induced Abeta sequestration to a similar or greater degree compared with intact antibodies in an Alzheimer's transgenic mouse model without or with Abeta plaque pathology. We conclude that deglycosylated antibodies effectively induced Abeta sequestration without provoking neuroinflammation; thus, these deglycosylated antibodies may be optimal for sequestration therapy for Alzheimer's disease.