Novel Players in the Aging Synapse: Impact on Cognition.

IF 1.7 Q4 Pharmacology, Toxicology and Pharmaceutics Journal of Caffeine and Adenosine Research Pub Date : 2019-09-01 Epub Date: 2019-09-17 DOI:10.1089/caff.2019.0013
Mariana Temido-Ferreira, Joana E Coelho, Paula A Pousinha, Luísa V Lopes
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Abstract

While neuronal loss has long been considered as the main contributor to age-related cognitive decline, these alterations are currently attributed to gradual synaptic dysfunction driven by calcium dyshomeostasis and alterations in ionotropic/metabotropic receptors. Given the key role of the hippocampus in encoding, storage, and retrieval of memory, the morpho- and electrophysiological alterations that occur in the major synapse of this network-the glutamatergic-deserve special attention. We guide you through the hippocampal anatomy, circuitry, and function in physiological context and focus on alterations in neuronal morphology, calcium dynamics, and plasticity induced by aging and Alzheimer's disease (AD). We provide state-of-the art knowledge on glutamatergic transmission and discuss implications of these novel players for intervention. A link between regular consumption of caffeine-an adenosine receptor blocker-to decreased risk of AD in humans is well established, while the mechanisms responsible have only now been uncovered. We review compelling evidence from humans and animal models that implicate adenosine A2A receptors (A2AR) upsurge as a crucial mediator of age-related synaptic dysfunction. The relevance of this mechanism in patients was very recently demonstrated in the form of a significant association of the A2AR-encoding gene with hippocampal volume (synaptic loss) in mild cognitive impairment and AD. Novel pathways implicate A2AR in the control of mGluR5-dependent NMDAR activation and subsequent Ca2+ dysfunction upon aging. The nature of this receptor makes it particularly suited for long-term therapies, as an alternative for regulating aberrant mGluR5/NMDAR signaling in aging and disease, without disrupting their crucial constitutive activity.

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衰老突触中的小说玩家:对认知的影响。
虽然神经元损失长期以来一直被认为是年龄相关认知能力下降的主要原因,但这些变化目前被归因于钙稳态失调和离子型/代谢型受体变化引起的逐渐突触功能障碍。鉴于海马体在记忆的编码、存储和检索中的关键作用,谷氨酸能网络的主要突触中发生的形态和电生理变化值得特别关注。我们在生理背景下指导您了解海马的解剖结构、电路和功能,并关注衰老和阿尔茨海默病(AD)引起的神经元形态、钙动力学和可塑性的变化。我们提供了谷氨酸能传递的最新知识,并讨论了这些新参与者对干预的影响。在人类中,经常摄入咖啡因(一种腺苷受体阻滞剂)与降低AD风险之间的联系已经得到了很好的证实,而其机制直到现在才被揭示。我们回顾了来自人类和动物模型的令人信服的证据,这些证据表明腺苷A2A受体(A2AR)激增是与年龄相关的突触功能障碍的关键介质。这一机制在患者中的相关性最近以A2AR编码基因与轻度认知障碍和AD患者海马体积(突触损失)的显著关联的形式得到了证实。新的途径表明A2AR在控制mGluR5依赖性NMDAR激活和随后衰老时的Ca2+功能障碍中发挥作用。这种受体的性质使其特别适合长期治疗,作为在衰老和疾病中调节异常mGluR5/NDAR信号的替代品,而不会破坏其关键的组成活性。
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