β-Amyloid neurotoxicity is mediated by a glutamate-triggered excitotoxic cascade in rat nucleus basalis
β-Amyloid neurotoxicity is mediated by a glutamate-triggered excitotoxic cascade in rat nucleus basalis
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DOI：
10.1046/j.1460-9568.2000.00164.x
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发表时间：
2000-08-01
影响因子：
3.4
通讯作者：
Luiten, PGM
中科院分区：
文献类型：
--
作者：
Harkany, T;Abrahám, I;Luiten, PGM
虽然β-淀粉样蛋白（A β）的主要作用已被假定为阿尔茨海默病中神经元损伤的主要触发因素，但A β扰乱神经细胞的致病机制在很大程度上仍然难以捉摸。在这里，我们报告相关的在体外和体内的证据表明，兴奋性级联介导的A β神经毒性在大鼠大细胞基底核（MBN）。体外应用A β刺激星形胶质细胞可使星形胶质细胞膜快速去极化，同时抑制谷氨酸摄取。通过微透析在MBN中的体内A β输注揭示了兴奋性氨基酸神经递质在20-30分钟内的峰值细胞外浓度。如Ca-45（2+）放射自显影所示，A β触发的兴奋性氨基酸的细胞外升高与A β注射区域中Ca 2+的显著增强的细胞内积聚相一致。在这些急性过程的结果，延迟细胞死亡的MBN和持续损失的胆碱能纤维投射到新皮层出现早在3天后，A β诱导的毒性损伤。N-甲基-d-天冬氨酸（NMDA）受体配体马来酸地佐环平（MK-801）可有效拮抗A β毒性的这种顺序。此外，MBN中的A β毒性随着年龄的增长而降低，这可能与大鼠中NMDA受体表达的年龄相关性丧失有关。总之，本研究结果表明，A β妥协的大鼠MBN神经元通过兴奋性毒性途径，包括星形胶质细胞去极化，细胞外谷氨酸积累，NMDA受体激活和细胞内Ca 2+超载导致细胞死亡。
Whereas a cardinal role for beta-amyloid protein (A beta) has been postulated as a major trigger of neuronal injury in Alzheimer's disease, the pathogenic mechanism by which A beta deranges nerve cells remains largely elusive. Here we report correlative in vitro and in vivo evidence that an excitotoxic cascade mediates A beta neurotoxicity in the rat magnocellular nucleus basalis (MBN). In vitro application of A beta to astrocytes elicits rapid depolarization of astroglial membranes with a concomitant inhibition of glutamate uptake. In vivo A beta infusion by way of microdialysis in the MBN revealed peak extracellular concentrations of excitatory amino acid neurotransmitters within 20-30 min. A beta-triggered extracellular elevation of excitatory amino acids coincided with a significantly enhanced intracellular accumulation of Ca2+ in the A beta injection area, as was demonstrated by Ca-45(2+) autoradiography. In consequence of these acute processes delayed cell death in the MBN and persistent loss of cholinergic fibre projections to the neocortex appear as early as 3 days following the A beta-induced toxic insult. Such a sequence of A beta toxicity was effectively antagonized by the N-methyl-d-aspartate (NMDA) receptor ligand dizocilpine maleate (MK-801). Moreover, A beta toxicity in the MBN decreases with advancing age that may be associated with the age-related loss of NMDA receptor expression in rats. In summary, the present results indicate that A beta compromises neurons of the rat MBN via an excitotoxic pathway including astroglial depolarization, extracellular glutamate accumulation, NMDA receptor activation and an intracellular Ca2+ overload leading to cell death.