1 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada 2 Sunnybrook Research Institute, Toronto, ON, Canada.
2 Sunnybrook Research Institute, Toronto, ON, Canada.
Brain. 2015 Apr;138(Pt 4):1046-58. doi: 10.1093/brain/awv023. Epub 2015 Feb 16.
Most patients with Alzheimer's disease exhibit accumulation of amyloid-β peptide on leptomeningeal and cortical arterioles, or cerebral amyloid angiopathy, which is associated with impaired vascular reactivity and accelerated cognitive decline. Despite widespread recognition of the significance of vascular dysfunction in Alzheimer's disease aetiology and progression, much uncertainty still surrounds the mechanism underlying Alzheimer's disease vascular injury. Studies to date have focused on amyloid-β-induced damage to capillaries and plaque-associated arterioles, without examining effects across the entire vascular bed. In the present study, we investigated the structural and functional impairment of the feeding arteriolar versus draining venular vessels in a transgenic murine Alzheimer's disease model, with a particular focus on the mural cell populations that dictate these vessels' contractility. Although amyloid-β deposition was restricted to arterioles, we found that vascular impairment extended to the venules, which showed significant depletion of their mural cell coverage by the mid-stage of Alzheimer's disease pathophysiology. These structural abnormalities were accompanied by an abolishment of the normal vascular network flow response to hypercapnia: this functional impairment was so severe as to result in hypercapnia-induced flow decreases in the arterioles. Further pharmacological depletion of mural cells using SU6668, a platelet-derived growth factor receptor-β antagonist, resulted in profound structural abnormalities of the cortical microvasculature, including vessel coiling and short-range looping, increased tortuosity of the venules but not of the arterioles, increased amyloid-β deposition on the arterioles, and further alterations of the microvascular network cerebral blood flow response to hypercapnia. Together, this work shows hitherto unrecognized structural alterations in penetrating venules, demonstrates their functional significance and sheds light on the complexity of the relationship between vascular network structure and function in Alzheimer's disease.
大多数阿尔茨海默病患者的软脑膜和皮质小动脉（或脑淀粉样血管病）存在淀粉样β肽积聚，这与血管反应性受损和认知能力加速下降有关。尽管人们普遍认识到血管功能障碍在阿尔茨海默病发病机制和进展中的重要性，但阿尔茨海默病血管损伤的机制仍存在很大的不确定性。迄今为止的研究主要集中在淀粉样β肽对毛细血管和斑块相关小动脉的损伤上，而没有检查整个血管床的影响。在本研究中，我们研究了转基因阿尔茨海默病小鼠模型中供养性小动脉与引流性小静脉血管的结构和功能损伤，特别关注决定这些血管收缩性的壁细胞群体。尽管淀粉样β肽沉积仅限于小动脉，但我们发现血管损伤延伸至小静脉，在阿尔茨海默病病理生理学的中期，小静脉的壁细胞覆盖率显著减少。这些结构异常伴随着正常血管网络对高碳酸血症反应的丧失：这种功能损伤非常严重，导致小动脉在高碳酸血症诱导下的血流量减少。使用血小板衍生生长因子受体-β拮抗剂 SU6668 进一步耗尽壁细胞，导致皮质微血管的严重结构异常，包括血管卷曲和短程环化、小静脉的迂曲增加但小动脉没有增加、小动脉上的淀粉样β沉积增加，以及对高碳酸血症反应的微血管网络脑血流的进一步改变。总之，这项工作显示了穿透性小静脉以前未被识别的结构改变，证明了它们的功能意义，并揭示了血管网络结构和功能之间关系的复杂性。
