School of Pharmacy, Shanghai Jiaotong University, China.
Biol Pharm Bull. 2012;35(2):131-8. doi: 10.1248/bpb.35.131.
The deposition of β-amyloid (Aβ) plaques and progressive loss of neurons are two main characteristics of Alzheimer's disease (AD). Supplement of neural stem/progenitor cells (NSPCs) is a promising strategy for repair of the neurodegenerative diseases. However, hostile microenvironment of neurodegenerative brain is harmful for the neuroregeneration. Aβ(42) promoted the proliferation of NSPCs. Moreover, Aβ(42) (10-1000 nM) promoted the migration of NSPCs in a dose-dependent manner. The attraction of NSPCs toward Aβ(42) was significantly offset by 10 μM cyclosporin H, a potent and selective formyl peptide receptor antagonist. After incubation with Aβ(42) for 9 d, the migration ability of NSPCs was significantly decreased (p<0.05). The expression of formyl peptide receptor (FPR) and CXC chemokine receptor-4 (CXCR4) were significantly decreased in NSPCs. The expression of G protein-coupled receptor kinase 2 (GRK2) was up-regulated on the membrane of NSPCs correspondingly. Our results suggested that Aβ(42) decreases the migratory capacity of NSPCs by FPR heterologous desensitization after long time incubation, and GRK2 in NSPCs may be responsible for the damaged migratory capacity.
β-淀粉样蛋白（Aβ）斑块的沉积和神经元的进行性丧失是阿尔茨海默病（AD）的两个主要特征。神经干细胞/祖细胞（NSPCs）的补充是修复神经退行性疾病的一种很有前途的策略。然而，神经退行性大脑的恶劣微环境对神经再生是有害的。Aβ（42）促进了 NSPCs 的增殖。此外，Aβ（42）（10-1000 nM）以剂量依赖的方式促进 NSPCs 的迁移。10 μM 环孢菌素 H（一种有效的、选择性的甲酰肽受体拮抗剂）显著抵消了 NSPCs 对 Aβ（42）的趋化作用。用 Aβ（42）孵育 9 天后，NSPCs 的迁移能力显著下降（p<0.05）。NSPCs 中 FPR 和 CXC 趋化因子受体-4（CXCR4）的表达显著下降。相应地，NSPCs 膜上的 G 蛋白偶联受体激酶 2（GRK2）表达上调。我们的结果表明，Aβ（42）通过长时间孵育后的 FPR 异源脱敏作用降低 NSPCs 的迁移能力，而 NSPCs 中的 GRK2 可能负责受损的迁移能力。
