PDF(Pubmed)
Abstract：
Cerebral amyloid angiopathy (CAA) is a vasculopathy characterized by vascular β-amyloid (Aβ) deposition on cerebral blood vessels. CAA is closely linked to Alzheimer\'s disease (AD) and intracerebral hemorrhage. CAA is associated with the loss of autoregulation in the brain, vascular rupture, and cognitive decline. To assess morphological and molecular changes associated with the degeneration of penetrating arterioles in CAA, we analyzed post-mortem human brain tissue from 26 patients with mild, moderate, and severe CAA end neurological controls. The tissue was optically cleared for three-dimensional light sheet microscopy, and morphological features were quantified using surface volume rendering. We stained Aβ, vascular smooth muscle (VSM), lysyl oxidase (LOX), and vascular markers to visualize the relationship between degenerative morphological features, including vascular dilation, dolichoectasia (variability in lumenal diameter) and tortuosity, and the volumes of VSM, Aβ, and LOX in arterioles. Atomic force microscopy (AFM) was used to assess arteriolar wall stiffness, and we identified a pattern of morphological features associated with degenerating arterioles in the cortex. The volume of VSM associated with the arteriole was reduced by around 80% in arterioles with severe CAA and around 60% in cases with mild/moderate CAA. This loss of VSM correlated with increased arteriolar diameter and variability of diameter, suggesting VSM loss contributes to arteriolar laxity. These vascular morphological features correlated strongly with Aβ deposits. At sites of microhemorrhage, Aβ was consistently present, although the morphology of the deposits changed from the typical organized ring shape to sharply contoured shards with marked dilation of the vessel. AFM showed that arteriolar walls with CAA were more than 400% stiffer than those without CAA. Finally, we characterized the association of vascular degeneration with LOX, finding strong associations with VSM loss and vascular degeneration. These results show an association between vascular Aβ deposition, microvascular degeneration, and increased vascular stiffness, likely due to the combined effects of replacement of VSM by β-amyloid, cross-linking of extracellular matrices (ECM) by LOX, and possibly fibrosis. This advanced microscopic imaging study clarifies the association between Aβ deposition and vascular fragility. Restoration of physiologic ECM properties in penetrating arteries may yield a novel therapeutic strategy for CAA.
摘要：
脑淀粉样血管病（CAA）是一种血管病变，其特征是脑血管上的血管β-淀粉样蛋白（Aβ）沉积。CAA与阿尔茨海默病(AD)和脑出血密切相关。CAA与大脑自动调节的丧失有关，血管破裂,和认知能力下降。为了评估与CAA中穿透性小动脉变性相关的形态和分子变化，我们分析了26例轻度，中度,和严重的CAA结束神经控制。对组织进行光学清除，进行三维光片显微镜检查，并使用表面体积绘制对形态特征进行量化。我们染色了Aβ,血管平滑肌（VSM），赖氨酰氧化酶（LOX），和血管标记物，以可视化退行性形态特征之间的关系，包括血管扩张,血管扩张(管腔直径的变异性)和弯曲,和VSM的体积，Aβ,和小动脉中的LOX。原子力显微镜（AFM）用于评估小动脉壁的刚度，我们发现了一种与皮质小动脉退化相关的形态特征。在患有严重CAA的小动脉中，与小动脉相关的VSM体积减少了约80％，在患有轻度/中度CAA的情况下约为60％。VSM的丢失与小动脉直径的增加和直径的变异性相关，提示VSM损失有助于小动脉松弛。这些血管形态特征与Aβ沉积物密切相关。在微出血部位，Aβ始终存在，尽管沉积物的形态从典型的有组织的环形变成了轮廓清晰的碎片，血管明显扩张。AFM显示，有CAA的小动脉壁比没有CAA的小动脉壁硬400％以上。最后,我们表征了血管变性与LOX的关系，发现与VSM丢失和血管变性密切相关。这些结果表明血管Aβ沉积之间的关联，微血管变性,血管僵硬度增加,可能是由于β-淀粉样蛋白替代VSM的综合作用，通过LOX交联细胞外基质（ECM），和可能的纤维化。这项先进的显微成像研究阐明了Aβ沉积与血管脆性之间的关联。在穿透动脉中恢复生理ECM特性可能产生新的CAA治疗策略。
