Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, Ontario, Canada.
Brain. 2012 Oct;135(Pt 10):3039-50. doi: 10.1093/brain/aws243.
The majority of patients with Alzheimer's disease have cerebral amyloid angiopathy, thus showing deposition of amyloid-β peptides in the walls of leptomeningeal and cortical arterioles. These deposits are believed to result from impaired clearance of parenchymal amyloid-β peptides. In the current work, we examined the changes in cortical microvascular structure and function in situ in TgCRND8, a transgenic mouse model of Alzheimer's disease. In contrast to venules, cortical arterioles were shown to increase in tortuosity and decrease in calibre with amyloid-β peptide accumulation. These structural changes were accompanied by progressive functional compromise, reflected in higher dispersion of microvascular network transit times, elongation of the transit times, and impaired microvascular reactivity to hypercapnia in the transgenic mice. Moreover, inhibition of amyloid-β peptide oligomerization and fibrillization via post-weaning administration of scyllo-inositol, a naturally occurring stereoisomer of myo-inositol, rescued both structural and functional impairment of the cortical microvasculature in this Alzheimer's disease model. These results demonstrate that microvascular impairment is directly correlated with amyloid-β accumulation and highlight the importance of targeting cerebrovascular amyloid angiopathy clearance for effective diagnosis, monitoring of disease progression and treatment of Alzheimer's disease.
大多数阿尔茨海默病患者都有脑淀粉样血管病，因此在软脑膜和皮质小动脉的壁上显示出淀粉样β肽的沉积。这些沉积物被认为是由于实质淀粉样β肽的清除受损所致。在目前的工作中，我们检查了阿尔茨海默病转基因小鼠模型 TgCRND8 中皮质微血管结构和功能的原位变化。与小静脉相比，随着淀粉样β肽的积累，皮质小动脉的迂曲度增加，口径减小。这些结构变化伴随着进行性的功能障碍，表现在微血管网络渡越时间的离散度增加、渡越时间延长以及对高碳酸血症的微血管反应性受损。此外，通过在断奶后给予 scyllo-肌醇（肌醇的天然立体异构体）抑制淀粉样β肽的寡聚化和纤维化，挽救了该阿尔茨海默病模型中小脑微血管的结构和功能损伤。这些结果表明微血管损伤与淀粉样β积累直接相关，并强调了靶向脑血管淀粉样血管病清除以进行有效诊断、监测疾病进展和治疗阿尔茨海默病的重要性。
