Identification of thyrotropin-releasing hormone as hippocampal glutaminyl cyclase substrate in neurons and reactive astrocytes.
Identification of thyrotropin-releasing hormone as hippocampal glutaminyl cyclase substrate in neurons and reactive astrocytes.
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DOI：
10.1016/j.bbadis.2014.11.011
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
A. Waniek;M. Hartlage-Rübsamen;C. Höfling;A. Kehlen;S. Schilling;H. Demuth;S. Roßner
中科院分区：
文献类型：
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作者：
A. Waniek;M. Hartlage-Rübsamen;C. Höfling;A. Kehlen;S. Schilling;H. Demuth;S. Roßner
最近，具有N-末端截短和焦谷氨酸修饰的Aβ肽变体被鉴定出，并且显示出高度神经毒性并且易于聚集。Aβ的这种修饰由β-氨基环化酶（QC）催化，药物抑制QC可减少Aβ沉积和伴随的神经胶质增生，并改善阿尔茨海默病（AD）转基因小鼠模型的记忆障碍。QC表达最初在下丘脑中描述，其中促甲状腺激素释放激素（TRH）是其生理底物之一。除了其激素作用外，还报道了TRH在兴奋性毒性和Aβ介导的神经毒性后在海马中的一种新的神经保护功能。与此发现相匹配的是，我们最近证实了小鼠脑中海马中间神经元的QC表达，在这里，我们使用双重免疫荧光标记检测了年轻成年野生型小鼠海马中QC和TRH的神经元共表达。这为TRH是海马中的生理QC底物提供了证据。此外，与野生型同窝出生小鼠相比，在淀粉样前体蛋白转基因老年小鼠而非年轻小鼠的新皮质中发现QC mRNA水平增加。在海马中未观察到这种现象，海马后来受到Aβ病理学的影响。然而，在转基因小鼠的海马体中-而不是野生型小鼠-QC和TRH mRNA水平之间的相关性被揭示。酶QC及其底物TRH的这种共调节通过Aβ沉积物附近的反应性星形胶质细胞中两种蛋白质的共诱导来反映。此外，在原代小鼠星形胶质细胞中，经Aβ刺激证实了QC和TRH的共诱导。
Recently, Aβ peptide variants with an N-terminal truncation and pyroglutamate modification were identified and shown to be highly neurotoxic and prone to aggregation. This modification of Aβ is catalyzed by glutaminyl cyclase (QC) and pharmacological inhibition of QC diminishes Aβ deposition and accompanying gliosis and ameliorates memory impairment in transgenic mouse models of Alzheimer's disease (AD). QC expression was initially described in the hypothalamus, where thyrotropin-releasing hormone (TRH) is one of its physiological substrates. In addition to its hormonal role, a novel neuroprotective function of TRH following excitotoxicity and Aβ-mediated neurotoxicity has been reported in the hippocampus. Functionally matching this finding, we recently demonstrated QC expression by hippocampal interneurons in mouse brain.Here, we detected neuronal co-expression of QC and TRH in the hippocampus of young adult wild type mice using double immunofluorescence labeling. This provides evidence for TRH being a physiological QC substrate in hippocampus. Additionally, in neocortex of aged but not of young mice transgenic for amyloid precursor protein an increase of QC mRNA levels was found compared to wild type littermates. This phenomenon was not observed in hippocampus, which is later affected by Aβ pathology. However, in hippocampus of transgenic — but not of wild type mice — a correlation between QC and TRH mRNA levels was revealed. This co-regulation of the enzyme QC and its substrate TRH was reflected by a co-induction of both proteins in reactive astrocytes in proximity of Aβ deposits. Also, in primary mouse astrocytes a co-induction of QC and TRH was demonstrated upon Aβ stimulation.