Department of Pharmacology, Division of Internal Medicine, Faculty of Medicine, Pamukkale University, Kinikli, Denizli 20070, Turkey.
Life Sci. 2013 Feb 27;92(3):228-36. doi: 10.1016/j.lfs.2012.12.004. Epub 2013 Jan 4.
Alzheimer's disease (AD) is characterized by vascular dysfunction, in addition to memory impairment. Previously we found that β-sheet breaker peptides (βSBPs) improved memory impairment induced by amyloid β-peptide Aβ40. In this study we investigated βSBP effects on vascular responses in a rat model of AD.
AD model was induced by bilateral injection of aged Aβ40 (3 nmol) into the amygdala. βSBPs 15-22, 16-23 and 17-24 (30 nmol) were injected into the amygdala 8 days after Aβ40. The Aβ40 deposits were examined immunohistochemically in cerebral vessels and thoracic aorta. The effects on high-K(+) contractility, phenylephrine (PE) contractility, acetylcholine (ACh) relaxation and sodium nitroprusside (SNP) relaxation were investigated in isolated thoracic aorta. Nitric oxide (NO) level in serum was investigated 14 days after Aβ40.
Aβ40 was localized and it induced vascular damage in minute and small perforating cerebral vascular endothelium, and tunica intima (endothelial) and media (smooth muscle cells) of the thoracic aorta. In intact aorta, ACh-relaxation was decreased by Aβ40, an effect reduced by βSBPs 15-22 and 16-23. In denuded aorta, Aβ40 decreased PE-contractility. βSBP15-22 increased ACh-relaxation, whereas βSBP17-24 increased K(+)-contraction. Aβ40 decreased NO, an effect inhibited by the βSBP15-22.
These results provide evidence that Aβ40-perverted endothelium-dependent relaxation and decreased serum NO in AD rats were improved differentially by the βSBP15-22. These results show the ability of Aβ40 to alter vascular responses. βSBPs appear to be promising candidate for prevention of these consequences and therapy of AD.
阿尔茨海默病（AD）的特征是血管功能障碍，除了记忆障碍。我们之前发现，β-折叠破坏肽（βSBPs）可改善由淀粉样β肽 Aβ40 引起的记忆障碍。在这项研究中，我们研究了βSBP 对 AD 大鼠模型中血管反应的影响。
通过双侧将老化的 Aβ40（3 毫摩尔）注射到杏仁核中来诱导 AD 模型。在 Aβ40 注射 8 天后，将βSBPs 15-22、16-23 和 17-24（30 毫摩尔）注射到杏仁核中。通过免疫组织化学检查大脑血管和胸主动脉中的 Aβ40 沉积物。在分离的胸主动脉中研究了高 K（+）收缩性、苯肾上腺素（PE）收缩性、乙酰胆碱（ACh）松弛和硝普钠（SNP）松弛的影响。在 Aβ40 后 14 天研究了血清中的一氧化氮（NO）水平。
Aβ40 定位并诱导微小和小穿孔性脑血管内皮以及胸主动脉的内膜（内皮）和中膜（平滑肌细胞）的血管损伤。在完整的主动脉中，Aβ40 可降低 ACh 松弛，而βSBPs 15-22 和 16-23 可减轻这种作用。在去内皮主动脉中，Aβ40 降低了 PE 收缩性。βSBP15-22 增加了 ACh 松弛，而βSBP17-24 增加了 K（+）收缩。Aβ40 降低了血清中的 NO，这种作用被βSBP15-22 抑制。
这些结果提供了证据，证明 Aβ40 改变的 AD 大鼠内皮依赖性松弛和血清中 NO 降低可通过βSBP15-22 得到不同程度的改善。这些结果表明 Aβ40 改变血管反应的能力。βSBPs 似乎是预防这些后果和治疗 AD 的有前途的候选药物。
