Department of Pathology, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China.
Cell Mol Neurobiol. 2012 Jan;32(1):141-7. doi: 10.1007/s10571-011-9744-8. Epub 2011 Aug 12.
The pathological hallmarks of Alzheimer's disease (AD) include formation of extracellular amyloid-β peptide (Aβ) and inflammatory responses. Numerous studies have reported that cerebral microvascular Aβ deposition promotes neuroinflammation in AD. Matrix metalloproteinases (MMPs) are involved in the cleavage of extracellular matrix proteins and regulation of growth factors, receptors, and adhesion molecules. Relatively little is known about the involvement of MMPs as inflammatory mediators in the pathological processes of AD. In this study, we explored the signaling pathway of MMP-2 up-regulation by Aβ in brain endothelial cells (BECs) of mice. Using Western blots, we found that inhibitors of extracellular-signal-regulated kinases (ERK) and c-Jun N-terminal kinase (JNK) significantly decreased Aβ-induced MMP-2 expression in BECs. Furthermore, antibody neutralization of the receptor for advanced glycation endproducts effectively blocked Aβ-induced activation of ERK and JNK and their contribution to elevated MMP-2 expression in BECs. Our results suggest that increased MMP-2 expression induced by the interaction of Aβ with RAGE in BECs may contribute to enhanced vascular inflammatory stress in Aβ-related vascular disorders, such as cerebral amyloid angiopathy and AD. This study offers new insights into neuroinflammation in the progression of AD.
阿尔茨海默病（AD）的病理特征包括细胞外淀粉样β肽（Aβ）的形成和炎症反应。许多研究报告称，脑微血管 Aβ 沉积促进了 AD 中的神经炎症。基质金属蛋白酶（MMPs）参与细胞外基质蛋白的切割以及生长因子、受体和粘附分子的调节。相对较少的研究涉及 MMPs 作为 AD 病理过程中的炎症介质。在这项研究中，我们探讨了 Aβ 在小鼠脑内皮细胞（BEC）中上调 MMP-2 的信号通路。通过 Western blot，我们发现细胞外信号调节激酶（ERK）和 c-Jun N-末端激酶（JNK）抑制剂显著降低了 Aβ诱导的 BEC 中 MMP-2 的表达。此外，晚期糖基化终产物受体的抗体中和有效地阻断了 Aβ 诱导的 ERK 和 JNK 的激活及其对 BEC 中 MMP-2 表达升高的贡献。我们的研究结果表明，Aβ 与 BEC 中的 RAGE 相互作用诱导的 MMP-2 表达增加可能导致与 Aβ 相关的血管疾病（如脑淀粉样血管病和 AD）中血管炎症应激增强。这项研究为 AD 进展中的神经炎症提供了新的见解。
