Department of Anatomy, Capital Medical University, Beijing, China.
J Alzheimers Dis. 2010;22(2):541-56. doi: 10.3233/JAD-2010-100948.
Soluble oligomeric amyloid-β (Aβ) is thought to induce synaptic dysfunction during early stages of Alzheimer's disease (AD). In this report, we show that soluble Aβ downregulates the levels of two synaptic proteins, PSD-95 and synaptophysin, and that this effect can be blocked by MK-801 (NMDAR antagonist) and ifenprodil (NR2B antagonist). Low (1 μM) and high (10 μM) doses of NMDA, respectively, prevented and potentiated the actions of Aβ. Blockade of NR2A or synaptic NMDAR eliminated the protective effect of 1 μM NMDA, while the effects of 10 μM NMDA were only abolished by ifenprodil. Caspase-8, acting upstream of caspase-3, was found to mediate the synaptotoxic actions of Aβ in an ifenprodil-reversible fashion. Thus, Aβ leads to a loss of synaptic proteins by suppression of NR2A function and activation of NR2B function and subsequent induction of caspase-8 and caspase-3 activities. The identified novel mechanism through which Aβ initiates synaptic dysfunction suggests that selective enhancement of NR2A activity and/or reduction of NR2B activity can halt the manifestation of a key early-stage event in AD.
可溶性寡聚体淀粉样蛋白-β（Aβ）被认为在阿尔茨海默病（AD）的早期阶段诱导突触功能障碍。在本报告中，我们表明可溶性 Aβ下调了两个突触蛋白 PSD-95 和突触小体素的水平，而这种作用可以被 MK-801（NMDAR 拮抗剂）和ifenprodil（NR2B 拮抗剂）阻断。低浓度（1 μM）和高浓度（10 μM）NMDA 分别预防和增强了 Aβ的作用。阻断 NR2A 或突触 NMDA 消除了 1 μM NMDA 的保护作用，而 10 μM NMDA 的作用仅被 ifenprodil 消除。发现半胱天冬酶-8（caspase-8）在 caspase-3 的上游起作用，以ifenprodil 可逆的方式介导 Aβ的突触毒性作用。因此，Aβ通过抑制 NR2A 功能和激活 NR2B 功能，以及随后诱导 caspase-8 和 caspase-3 活性，导致突触蛋白的丧失。确定的 Aβ引发突触功能障碍的新机制表明，选择性增强 NR2A 活性和/或降低 NR2B 活性可以阻止 AD 中一个关键早期事件的表现。
