Age-dependent cerebrovascular dysfunction in a transgenic mouse model of cerebral amyloid angiopathy
Age-dependent cerebrovascular dysfunction in a transgenic mouse model of cerebral amyloid angiopathy
复制标题
DOI：
10.1093/brain/awm156
复制
发表时间：
2007-09-01
期刊：
影响因子：
14.5
通讯作者：
Ayata, Cenk
中科院分区：
文献类型：
--
作者：
Shin, Hwa Kyoung;Jones, Phillip B.;Ayata, Cenk
Tg2576转基因小鼠的人脑淀粉样血管病模型的特征是从9个月龄开始脑血管淀粉样β蛋白(Ab)的年龄依赖性沉积，到18个月时逐渐恶化到累及大部分软脑膜小动脉；在该模型中，可溶性Aβ水平在血管沉积发生之前很久就会升高。已有研究表明，仅可溶性Aβ水平升高就足以损害脑血流(CBF)调节，从而导致阿尔茨海默病的早期进展。我们使用激光散斑血流仪通过完整的头骨，研究了升高的可溶性Aβ水平和血管Aβ沉积对广泛的CBF反应的影响，以评估年轻或老年Tg2576小鼠的血管扩张和血管收缩。与野生型相比，19个月大的患有严重血管Aβ沉积的Tg2576在高碳酸血症和胡须刺激时表现出较弱的充血反应。异氟醚麻醉引起的预期的CBF增加也被抑制，在皮质扩散抑制和α-氯醛糖麻醉期间典型的低灌流反应也受到抑制。8个月大的Tg2576有升高的可溶性Aβ水平，但没有血管抗体沉积，与年龄匹配的对照组没有区别。总而言之，我们的数据表明，血管Aβ沉积与血管扩张剂受损以及对广泛刺激的血管收缩反应有关。当在血管Aβ沉积之前进行非侵入性研究时，这些反应与对照组没有不同，因此挑战了这样的观点，即升高的可溶性Aβ水平足以导致脑血管功能障碍。
The Tg2576 transgenic mouse model of human cerebral amyloid angiopathy is characterized by age-dependent cerebrovascular deposition of amyloid-beta ( Ab) starting from 9 months of age and progressively worsening to involve most pial arterioles by 18 months; soluble A beta levels are elevated long before vascular deposition takes place in this model. It has been suggested that elevated soluble A beta levels alone are sufficient to impair cerebral blood flow (CBF) regulation thereby contributing to the early progression of Alzheimer's disease. Using laser speckle flowmetry through an intact skull, we studied the impact of elevated soluble A beta levels and vascular A beta deposition on a wide range of CBF responses to evaluate vasodilation and vasoconstriction in young or aged Tg2576 mice. Nineteen-month-old Tg2576 with severe vascular A beta deposits showed an attenuated hyperaemic response during hypercapnia and whisker stimulation compared to wild-type littermates. The anticipated increase in CBF due to isoflurane anaesthesia was also suppressed, as were the typical hypoperfusion responses during cortical spreading depression and alpha-chloralose anaesthesia. The responses of 8-month-old Tg2576 with elevated soluble A beta levels, but without vascular Ab deposition, did not differ fromage-matched controls. In conclusion, our data suggest that vascular A beta deposition is associated with impaired vasodilator as well as vasoconstrictor responses to a wide range of stimuli. These responses do not differ from controls when studied non-invasively prior to vascular A beta deposition, thus challenging the view that elevated soluble A beta levels are sufficient to cause cerebrovascular dysfunction.