Centre de Psychiatrie et de Neurosciences, INSERM U894, Université Paris-Descartes, 102 rue la Santé, 75014, Paris, France.
Laboratoire Aimé Cotton, ENS-Cachan, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 91405, Orsay, France.
Neurochem Res. 2019 Mar;44(3):692-702. doi: 10.1007/s11064-018-2677-6. Epub 2018 Nov 13.
Aging, as the major risk factor of Alzheimer's disease (AD), may increase susceptibility to neurodegenerative diseases through many gradual molecular and biochemical changes. Extracellular glutamate homeostasis and extrasynaptic glutamate N-methyl-D-aspartate receptors (NMDAR) are among early synaptic targets of oligomeric amyloid β (Aβo), one of the AD related synaptotoxic protein species. In this study, we asked for the effects of Aβo on long-term depression (LTD), a form of synaptic plasticity dependent on extrasynaptic NMDAR activation, and on a tonic current (TC) resulting from the activation of extrasynaptic NMDAR by ambient glutamate in hippocampal slices from young (3-6-month-old) and aged (24-28-month-old) Sprague-Dawley rats. Aβo significantly enhanced the magnitude of LTD and the amplitude of TC in aged slices compared to young ones. TBOA, a glutamate transporter inhibitor, also significantly increased LTD magnitude and TC amplitude in slices from aged rats, suggesting either an age-related weakness of the glutamate clearance system and/or a facilitated extrasynaptic NMDAR activation. From our present data, we hypothesize that senescence-related impairment of the extrasynaptic environment may be a vector of vulnerability of the aged hippocampus to neurodegenerative promotors such as Aβo.
衰老是阿尔茨海默病（AD）的主要风险因素，它可能通过许多逐渐的分子和生化变化增加神经退行性疾病的易感性。细胞外谷氨酸稳态和细胞外谷氨酸 N-甲基-D-天冬氨酸受体（NMDAR）是寡聚淀粉样β（Aβo）的早期突触靶点之一，Aβo 是与 AD 相关的突触毒性蛋白之一。在这项研究中，我们研究了 Aβo 对长时程抑制（LTD）的影响，LTD 是一种依赖于细胞外 NMDAR 激活的突触可塑性形式，以及由环境谷氨酸激活细胞外 NMDAR 引起的持续电流（TC），这些在来自年轻（3-6 个月大）和年老（24-28 个月大）Sprague-Dawley 大鼠的海马切片中进行。与年轻切片相比，Aβo 显著增强了年老切片中的 LTD 幅度和 TC 幅度。谷氨酸转运体抑制剂 TBOA 也显著增加了年老大鼠切片中的 LTD 幅度和 TC 幅度，这表明谷氨酸清除系统的年龄相关性减弱和/或细胞外 NMDAR 激活的促进。根据我们目前的数据，我们假设与衰老相关的细胞外环境损伤可能是年老海马体对神经退行性促进剂（如 Aβo）易感性的一个因素。
