Overexpression of Glutaminyl Cyclase, the Enzyme Responsible for Pyroglutamate Aβ Formation, Induces Behavioral Deficits, and Glutaminyl Cyclase Knock-out Rescues the Behavioral Phenotype in 5XFAD Mice
Overexpression of Glutaminyl Cyclase, the Enzyme Responsible for Pyroglutamate Aβ Formation, Induces Behavioral Deficits, and Glutaminyl Cyclase Knock-out Rescues the Behavioral Phenotype in 5XFAD Mice
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DOI：
10.1074/jbc.m110.185819
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发表时间：
2011-02-01
影响因子：
4.8
通讯作者：
Bayer, Thomas A.
中科院分区：
文献类型：
--
作者：
Jawhar, Sadim;Wirths, Oliver;Bayer, Thomas A.
焦谷氨酸修饰的A β (A β pE3-42)肽由于其在阿尔茨海默病（AD）脑中的丰度、高聚集倾向、稳定性和细胞毒性，作为阿尔茨海默病（AD）病理中的潜在关键角色，正受到越来越多的关注。过表达A β pE3-42在TBA2小鼠中诱导了严重的神经元丢失和神经表型。体外和体内实验最近证明了谷氨酰环化酶（QC）催化A β pE3-42的形成。本工作的目的是分析QC在具有丰富的A β pE3-42形成的AD小鼠模型中的作用。在Thy1启动子的控制下，将5XFAD小鼠与表达人QC （hQC）的转基因小鼠杂交。5XFAD/hQC双基因小鼠TBS、SDS、甲酸可溶性A β pE3-42肽和斑块聚集显著升高。在6个月大的5XFAD/hQC小鼠中，与5XFAD相比，出现了明显的运动和工作记忆障碍。通过产生5XFAD/QC- ko小鼠（小鼠QC敲除）来研究内源性QC的贡献。5XFAD/QC- ko小鼠表现出对野生型小鼠行为表型的显著拯救，证明了内源性小鼠QC和转基因过表达QC的重要贡献。这些数据清楚地表明，QC对体内A β pE3-42水平的调节至关重要，并在遗传学基础上证明了降低QC活性是一种有希望的治疗AD的新方法。
Pyroglutamate-modified A beta (A beta pE3-42) peptides are gaining considerable attention as potential key players in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Overexpressing A beta pE3-42 induced a severe neuron loss and neurological phenotype in TBA2 mice. In vitro and in vivo experiments have recently proven that the enzyme glutaminyl cyclase (QC) catalyzes the formation of A beta pE3-42. The aim of the present work was to analyze the role of QC in an AD mouse model with abundant A beta pE3-42 formation. 5XFAD mice were crossed with transgenic mice expressing human QC (hQC) under the control of the Thy1 promoter. 5XFAD/hQC bigenic mice showed significant elevation in TBS, SDS, and formic acid-soluble A beta pE3-42 peptides and aggregation in plaques. In 6-month-old 5XFAD/hQC mice, a significant motor and working memory impairment developed compared with 5XFAD. The contribution of endogenous QC was studied by generating 5XFAD/QC-KO mice (mouse QC knock-out). 5XFAD/QC-KO mice showed a significant rescue of the wild-type mice behavioral phenotype, demonstrating the important contribution of endogenous mouse QC and transgenic overexpressed QC. These data clearly demonstrate that QC is crucial for modulating A beta pE3-42 levels in vivo and prove on a genetic base the concept that reduction of QC activity is a promising new therapeutic approach for AD.