在一项新的研究中，来自葡萄牙分子医学研究所和法国国家健康与医学研究院等机构的研究人员揭示出咖啡因抵抗动物体内年龄相关性认知缺陷的机制。相关研究结果于2016年8月11日在线发表在自然出版集团旗下的Scientific Reports期刊上，论文标题为“The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function”。
研究人员证实在大鼠大脑中的一种特定受体---腺苷A2A受体（adenosine A2A receptor, A2AR），是咖啡因的靶标---的异常表达会诱导一种类似衰老的情形，也就是与应激控制机制丧失相关联的记忆缺陷。
论文共同通信作者、葡萄牙分子医学研究所研究团队领导Luisa Lopes解释道，“这是4年前启动的一项大型研究的一部分，在那项研究中，我们已鉴定出这种受体在应激中所发挥的作用，但是我们并不知道它的激活是否足以触发这些所有的变化发生。我们如今发现仅仅改变来自海马体和皮层---记忆相关区域---的神经元中的这种受体的水平就足以诱导我们称之为‘早衰（early-aging）’的情形：记忆丧失和血浆中应激激素（皮质醇）增加。”
当利用一种阻断A2AR发挥作用的咖啡因类似物治疗这些相同的动物时，记忆缺陷和应激相关缺陷都正常化。
论文共同通信作者、法国国家健康与医学研究院研究主任David Blum补充道，“我们知道在老年人中，对记忆产生影响的应激激素水平在增加。我们的研究支持这样的一种观点：A2AR拮抗剂，也就是咖啡因，在阿尔茨海默病和年龄相关性认知损伤中观察到的促进认知效应（procognitive effect）可能依赖于它的这种抵抗在衰老时发生的应激控制机制丧失的能力。”
Luisa Lopes作出结论，“这不仅对理解衰老时发生的基本变化是重要的，而且它也鉴定出A2AR功能障碍是触发这些变化的一种关键因子。它是一种非常吸引人的治疗靶标。”
The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function
Vania L. Batalha, Diana G. Ferreira, Joana E. Coelho, Jorge S. Valadas, Rui Gomes, Mariana Temido-Ferreira, Tatiana Shmidt, Younis Baqi, Luc Buée, Christa E. Müller, Malika Hamdane, Tiago F. Outeiro, Michael Bader, Sebastiaan H. Meijsing, Ghazaleh Sadri-Vakili, David Blum & Luísa V. Lopes
doi:10.1038/srep31493
PMC:
PMID:
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.