Kozberg Mariel G, Munting Leon P, Maresco Lee H, Auger Corinne A, van den Berg Maarten L, Denis de Senneville Baudouin, Hirschler Lydiane, Warnking Jan M, Barbier Emmanuel L, Farrar Christian T, Greenberg Steven M, Bacskai Brian J, van Veluw Susanne J
bioRxiv. 2024 Apr 30:2024.04.26.591414. doi: 10.1101/2024.04.26.591414.
Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease in which amyloid-β accumulates in vessel walls. CAA is a leading cause of symptomatic lobar intracerebral hemorrhage and an important contributor to age-related cognitive decline. Recent work has suggested that vascular dysfunction may precede symptomatic stages of CAA, and that spontaneous slow oscillations in arteriolar diameter (termed vasomotion), important for amyloid-β clearance, may be impaired in CAA.
To systematically study the progression of vascular dysfunction in CAA, we used the APP23 mouse model of amyloidosis, which is known to develop spontaneous cerebral microbleeds mimicking human CAA. Using 2-photon microscopy, we longitudinally imaged unanesthetized APP23 transgenic mice and wildtype littermates from 7 to 14 months of age, tracking amyloid-β accumulation and vasomotion in individual pial arterioles over time. MRI was used in separate groups of 12-, 18-, and 24-month-old APP23 transgenic mice and wildtype littermates to detect microbleeds and to assess cerebral blood flow and cerebrovascular reactivity with pseudo-continuous arterial spin labeling.
We observed a significant decline in vasomotion with age in APP23 mice, while vasomotion remained unchanged in wildtype mice with age. This decline corresponded in timing to initial vascular amyloid-β deposition (∼8-10 months of age), although was more strongly correlated with age than with vascular amyloid-β burden in individual arterioles. Declines in vasomotion preceded the development of MRI-visible microbleeds and the loss of smooth muscle actin in arterioles, both of which were observed in APP23 mice by 18 months of age. Additionally, evoked cerebrovascular reactivity was intact in APP23 mice at 12 months of age, but significantly lower in APP23 mice by 24 months of age.
Our findings suggest that a decline in spontaneous vasomotion is an early, potentially pre-symptomatic, manifestation of CAA and vascular dysfunction, and a possible future treatment target.
脑淀粉样血管病（CAA）是一种脑小血管疾病，其中淀粉样β蛋白在血管壁中积聚。CAA是有症状的叶脑出血的主要原因，也是与年龄相关的认知衰退的重要促成因素。最近的研究表明，血管功能障碍可能先于CAA的症状阶段出现，并且对淀粉样β蛋白清除很重要的小动脉直径的自发缓慢振荡（称为血管运动）在CAA中可能受损。
为了系统地研究CAA中血管功能障碍的进展，我们使用了淀粉样变性的APP23小鼠模型，已知该模型会出现模仿人类CAA的自发性脑微出血。使用双光子显微镜，我们对7至14个月大的未麻醉的APP23转基因小鼠和野生型同窝小鼠进行纵向成像，随时间追踪单个软脑膜小动脉中的淀粉样β蛋白积累和血管运动。在单独的12、18和24个月大的APP23转基因小鼠和野生型同窝小鼠组中使用MRI来检测微出血，并通过伪连续动脉自旋标记评估脑血流量和脑血管反应性。
我们观察到APP23小鼠的血管运动随年龄显著下降，而野生型小鼠的血管运动随年龄保持不变。这种下降在时间上与最初的血管淀粉样β蛋白沉积（约8至10个月大）相对应，尽管与年龄的相关性比与单个小动脉中的血管淀粉样β蛋白负荷的相关性更强。血管运动的下降先于MRI可见的微出血的出现和小动脉中平滑肌肌动蛋白的丧失，这两者在18个月大的APP23小鼠中都被观察到。此外，12个月大的APP23小鼠中诱发的脑血管反应性是完整的，但24个月大的APP23小鼠中则显著降低。
我们的研究结果表明，自发血管运动的下降是CAA和血管功能障碍的早期、潜在的症状前表现，并且可能是未来的治疗靶点。
