MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown Navy Yard, MA, USA.
J. Philip Kistler Stroke Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
J Cereb Blood Flow Metab. 2021 Jan;41(1):82-91. doi: 10.1177/0271678X19899377. Epub 2020 Jan 27.
The pathophysiology of microhemorrhages in the context of cerebral amyloid angiopathy (CAA) remains poorly understood. Here we used in vivo two-photon microscopy in aged APP/PS1 mice with mild-to-moderate CAA to assess the formation of microhemorrhages and their spatial relationship with vascular Aβ depositions in the surrounding microvascular network. Mice with chronic cranial windows were intravenously injected with fluorescent dextran to visualize the vessels and a fluorescently labeled anti-fibrin antibody to visualize microhemorrhages. Focal vessel irradiations resulted in extravascular fibrin-positive clots at individual rupture sites that remained visible for weeks. Spontaneous extravascular fibrin-positive clots were more often observed in 19-month-old transgenic APP/PS1 mice compared to their wild-type littermate controls ( = 0.039), after heparin administration. In the transgenic mice, these spontaneous leakage sites frequently occurred at arteriolar segments without CAA at bifurcations or vessel bends. These findings suggest that the presence of vascular Aβ per se does not directly predispose vessels to leak, but that complex flow dynamics within CAA-affected vascular networks likely play a role. Our in vivo approach for the detection of individual spontaneous leakage sites may be used in longitudinal studies aimed to assess structural and functional alterations at the single-vessel level leading up to microhemorrhage formation.
脑淀粉样血管病（Cerebral Amyloid Angiopathy，CAA）中小出血的病理生理学仍知之甚少。在这里，我们使用 aged APP/PS1 小鼠中的体内双光子显微镜，评估了轻度至中度 CAA 中小出血的形成及其与周围微血管网络中血管 Aβ 沉积的空间关系。有慢性颅窗的小鼠经静脉注射荧光葡聚糖以可视化血管，并注射荧光标记的抗纤维蛋白抗体以可视化微出血。局部血管辐照导致在单个破裂部位形成血管外纤维蛋白阳性血栓，这些血栓在数周内仍然可见。与野生型同窝对照相比，19 个月大的转基因 APP/PS1 小鼠中自发性血管外纤维蛋白阳性血栓更为常见（=0.039），肝素给药后更是如此。在转基因小鼠中，这些自发性渗漏部位常发生在没有 CAA 的分叉处或血管弯曲处的小动脉段。这些发现表明，血管 Aβ 的存在本身并不会使血管直接易于渗漏，但 CAA 相关血管网络中复杂的流动动力学可能发挥了作用。我们用于检测单个自发性渗漏部位的体内方法可用于纵向研究，旨在评估导致微出血形成的单个血管水平的结构和功能改变。
