Department of Biology, University of Virginia, Charlottesville, VA, USA.
Department of Biology, University of Virginia, Charlottesville, VA, USA.
Alzheimers Dement. 2018 Oct;14(10):1302-1312. doi: 10.1016/j.jalz.2018.05.017. Epub 2018 Jul 4.
Alzheimer's disease (AD) symptoms reflect synaptic dysfunction and neuron death. Amyloid-β oligomers (AβOs) induce excess calcium entry into neurons via N-methyl-D-aspartate receptors (NMDARs), contributing to synaptic dysfunction. The study described here tested the hypothesis that AβO-stimulated calcium entry also drives neuronal cell cycle reentry (CCR), a prelude to neuron death in AD.
Pharmacologic modulators of calcium entry and gene expression knockdown were used in cultured neurons and AD model mice.
In cultured neurons, AβO-stimulated CCR was blocked by NMDAR antagonists, total calcium chelation with 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM), or knockdown of the NMDAR subunit, NR1. NMDAR antagonists also blocked the activation of calcium-calmodulin-dependent protein kinase II and treatment of Tg2576 AD model mice with the NMDAR antagonist, memantine, prevented CCR.
This study demonstrates a role for AβO-stimulated calcium influx via NMDAR and CCR in AD and suggests the use of memantine as a disease-modifying therapy for presymptomatic AD.
阿尔茨海默病（AD）的症状反映了突触功能障碍和神经元死亡。淀粉样β寡聚物（AβOs）通过 N-甲基-D-天冬氨酸受体（NMDARs）诱导神经元中过量的钙内流，导致突触功能障碍。本研究假设 AβO 刺激的钙内流也会驱动神经元细胞周期再进入（CCR），这是 AD 中神经元死亡的前奏。
在培养的神经元和 AD 模型小鼠中使用钙内流的药理学调节剂和基因表达敲低。
在培养的神经元中，NMDAR 拮抗剂、总钙螯合剂 1,2-双（2-氨基苯氧基）乙烷-N,N,N',N'-四乙酸四（乙酰氧甲基酯）（BAPTA-AM）或 NMDAR 亚基 NR1 的基因敲低均可阻断 AβO 刺激的 CCR。NMDAR 拮抗剂还阻断了钙调蛋白依赖性蛋白激酶 II 的激活，用 NMDAR 拮抗剂美金刚治疗 Tg2576 AD 模型小鼠可防止 CCR。
本研究表明 AβO 刺激的 NMDAR 钙内流和 CCR 在 AD 中的作用，并提示使用美金刚作为 AD 前症状的疾病修饰治疗。
