Amyloid-β-dependent compromise of microvascular structure and function in a model of Alzheimer's disease
Amyloid-β-dependent compromise of microvascular structure and function in a model of Alzheimer's disease
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DOI：
10.1093/brain/aws243
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发表时间：
2012-10-01
期刊：
影响因子：
14.5
通讯作者：
Stefanovic, Bojana
中科院分区：
文献类型：
--
作者：
Dorr, Adrienne;Sahota, Bhupinder;Stefanovic, Bojana
大多数阿尔茨海默病患者患有脑淀粉样血管病，因此在小脑膜和皮质小动脉壁上沉积淀粉样肽。这些沉积被认为是由于实质淀粉样肽清除受损所致。在目前的工作中，我们原位检测了阿尔茨海默病转基因小鼠模型TgCRND8的皮质微血管结构和功能的变化。与小静脉相比，皮质小动脉弯曲度增加，淀粉样蛋白- β肽积累使其直径减小。这些结构变化伴随着进行性功能损害，反映在转基因小鼠微血管网络传递时间的分散性增加，传递时间的延长以及微血管对高碳酸血症的反应性受损。此外，在该老年痴呆症模型中，通过断奶后给药三基肌醇（一种天然存在的肌肌醇立体异构体）抑制淀粉样β肽寡聚化和纤维化，可以挽救皮质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蛋白- β积累直接相关，并强调了靶向脑血管淀粉样蛋白血管病变清除对于有效诊断、监测疾病进展和治疗阿尔茨海默病的重要性。
The majority of patients with Alzheimer's disease have cerebral amyloid angiopathy, thus showing deposition of amyloid-beta peptides in the walls of leptomeningeal and cortical arterioles. These deposits are believed to result from impaired clearance of parenchymal amyloid-beta 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-beta 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-beta 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-beta accumulation and highlight the importance of targeting cerebrovascular amyloid angiopathy clearance for effective diagnosis, monitoring of disease progression and treatment of Alzheimer's disease.