The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function.
The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function.
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DOI：
10.1038/srep31493
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发表时间：
2016-08-11
影响因子：
4.6
通讯作者：
Lopes LV
中科院分区：
文献类型：
--
作者：
Batalha VL;Ferreira DG;Coelho JE;Valadas JS;Gomes R;Temido-Ferreira M;Shmidt T;Baqi Y;Buée L;Müller CE;Hamdane M;Outeiro TF;Bader M;Meijsing SH;Sadri-Vakili G;Blum D;Lopes LV
咖啡因通过抵消腺苷 A2A 受体 (A2AR) 的过度激活而与人类的促认知作用相关，腺苷 A2A 受体 (A2AR) 在老年人和阿尔茨海默病 (AD) 患者的人类前脑中表达上调。我们之前已经证明，抗 A2AR 疗法通过重建下丘脑-垂体-肾上腺 (HPA) 轴反馈和皮质酮昼夜节律水平来恢复年龄样记忆缺陷。这些观察结果表明，A2AR 过度激活和糖皮质激素功能障碍是与年龄相关的海马缺陷的关键事件。但它们之间的直接联系从未被探索过。我们现在表明，在类似衰老的情况下诱导 A2AR 过度表达足以触发 HPA 轴功能障碍，即血浆皮质酮昼夜节律振荡的丧失，并促进 GR 海马水平的降低。海马区 GR 引发的突触可塑性和记忆缺陷会因 A2AR 过度激活而放大，并可通过抗 A2AR 治疗得到缓解；最后，我们证明 A2AR 作用于 GR 核易位和 GR 依赖性转录调控。我们首次证明 A2AR 是 GR 功能的主要调节因子，并且这种功能互连可能会触发与年龄相关的记忆缺陷。这支持了这样一种观点，即 A2AR 拮抗剂（即咖啡因）对阿尔茨海默病和年龄相关认知障碍的促认知作用可能依赖于其调节 GR 作用的能力。
Caffeine is associated with procognitive effects in humans by counteracting overactivation of the adenosine A2A receptor (A2AR), which is upregulated in the human forebrain of aged and Alzheimer’s disease (AD) patients. We have previously shown that an anti-A2AR therapy reverts age-like memory deficits, by reestablishment of the hypothalamic-pituitary-adrenal (HPA) axis feedback and corticosterone circadian levels. These observations suggest that A2AR over-activation and glucocorticoid dysfunction are key events in age-related hippocampal deficits; but their direct connection has never been explored. We now show that inducing A2AR overexpression in an aging-like profile is sufficient to trigger HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and promotes reduction of GR hippocampal levels. The synaptic plasticity and memory deficits triggered by GR in the hippocampus are amplified by A2AR over-activation and were rescued by anti-A2AR therapy; finally, we demonstrate that A2AR act on GR nuclear translocation and GR-dependent transcriptional regulation. We provide the first demonstration that A2AR is a major regulator of GR function and that this functional interconnection may be a trigger to age-related memory deficits. This supports the idea that the procognitive effects of A2AR antagonists, namely caffeine, on Alzheimer’s and age-related cognitive impairments may rely on its ability to modulate GR actions.