中国神经再生研究(英文版) ›› 2015, Vol. 10 ›› Issue (2): 213-218.doi: 10.4103/1673-5374.152373

• 综述:退行性病与再生 • 上一篇    下一篇

人类星形胶质细胞和神经元中拮抗beta淀粉样蛋白/钙敏感受体信号:是阿尔茨海默病的停止键?

  

  • 收稿日期:2015-01-12 出版日期:2015-02-17 发布日期:2015-02-17

Antagonizing amyloid-β/calcium-sensing receptor signaling in human astrocytes and neurons: a key to halt Alzheimer’s disease progression?

Ilaria Dal Prà, Anna Chiarini, Ubaldo Armato   

  1. Histology & Embryology Section, Department of Life & Reproduction Sciences, University of Verona Medical School, Verona, Venetia, I-37134, Italy
  • Received:2015-01-12 Online:2015-02-17 Published:2015-02-17
  • Contact: Ubaldo Armato, M.D., uarmato@gmail.com.

摘要:

阿尔茨海默病是一种慢性神经退行性疾病,其病情的逐渐进展会导致死亡。最近,迄今失败的阿尔茨海默病治疗前景已经得到改变:钙受体拮抗剂或选择性钙敏感受体拮抗剂能够有效地抑制人类皮层成人星形胶质细胞和神经元内的外源淀粉样蛋白β42低聚物(Aβ42-OS)诱导的内源性Aβ42-OS过释放。因此,溶解钙应该能够停止“蔓延性”阿尔茨海默病进展,保留神经元的认知和生存能力,进而保障和延长病患的生活质量和寿命。偶发性阿尔茨海默病发生在横向嗅皮层,是一种“蔓延性”过程,逐步扩散并破坏大脑皮层上部的认知相关领域。越来越多的证据支持这样一种观点,即Aβ42低聚物(Aβ42-OS)和tau蛋白低聚物(P-τ-OS)是阿尔茨海默病神经病理学特征的主要驱动因素。看起来,tau蛋白低聚物是通过Aβ42-OS的活动首先出现在阿尔茨海默病病程下游。根据当前的主要观点,这两种阿尔茨海默病驱动因素主要由神经元产生,而与他们密切相关的星形细胞团队只会充当看门人,负责碎屑清除和/或启动并发神经炎症。迄今还没有治疗能够阻止阿尔茨海默病的致命过程。细胞外累积Aβ42低聚物会结合未转换的人类大脑皮层成人星形胶质细胞的钙敏感受体以及产后体外培养神经元,并激活它们的细胞内信号通路。后者会触发:(1)神经元和星形胶质细胞的内源性Aβ42-OS过量分泌;(2)剩余即一氧化氮神经毒性释放,以及星形胶质细胞的血管内皮生长因子-A;(3)渐进性神经元死亡,而星形胶质细胞会存活并保持产生上述的三个神经毒素。然而,正如Armato教授和其同事指出的,加入高选择性和特异性变构钙敏感受体拮抗剂(或溶解钙)后,如NPS2143,其能经人类神经元和星形胶质细胞的Aβ42-OS/CaSR病理信号有效地抑制所有(1-3)带来的影响。由于这些原因,Armato教授和同事进一步提出,该溶解钙应该能够阻止Aβ42低聚物扩散和紧密耦合神经元星形胶质细胞的神经毒性累积,通过保持神经元存活和运行,保护患者的认知能力,生活质量和寿命。最后,Armato教授和同事表示,希望溶解钙能够尽快作为抗阿尔茨海默病药物进行临床前研究并进入临床试验阶段。

Abstract:

Astrocytes’ roles in late-onset Alzheimer’s disease (LOAD) promotion are important, since they survive soluble or fibrillar amyloid-β peptides (Aβs) neurotoxic effects, undergo alterations of intracellular and intercellular Ca2+ signaling and gliotransmitters release via the Aβ/α7-nAChR (α7-nicotinic acetylcholine receptor) signaling, and overproduce/oversecrete newly synthesized Aβ42 oligomers, NO, and VEGF-A via the Aβ/CaSR (calcium-sensing receptor) signaling. Recently, it was suggested that the NMDAR (N-methyl-D-aspartate receptor) inhibitor nitromemantine would block the synapse-destroying effects of Aβ/α7-nAChR signaling. Yet, this and the progressive extracellular accrual and spreading of Aβ42 oligomers would be stopped well upstream by NPS 2143, an allosteric CaSR antagonist (calcilytic).

Key words: Alzheimer’s disease, amyloid-β, astrocytes, Ca2+, calcilytic, calcium-sensing receptor, nitromemantine, NPS 2143, α7-nicotinic acetylcholine receptor