ADAMTS13 maintains cerebrovascular integrity to ameliorate Alzheimer-like pathology (Retracted article. See vol. 21, 2023)
ADAMTS13 maintains cerebrovascular integrity to ameliorate Alzheimer-like pathology (Retracted article. See vol. 21, 2023)
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ADAMTS13 维持脑血管完整性以改善阿尔茨海默样病理
DOI：
10.1371/journal.pbio.3000313
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发表时间：
2019-06-01
期刊：
影响因子：
9.8
通讯作者：
Fan, Wenying
中科院分区：
文献类型：
--
作者：
Cao, Yongliang;Xu, Haochen;Fan, Wenying
血脑屏障（BBB）缺陷和脑血管功能障碍导致淀粉样蛋白β（A β）脑内蓄积并导致阿尔茨海默病（AD）病理学改变。通过调节微血管系统中的血管功能和炎症，具有血小板反应蛋白I型基序的解整合素和金属蛋白酶，成员13（ADAMTS13）在动脉粥样硬化和中风中发挥显著的保护作用。然而，ADAMTS13是否影响AD发病机制仍不清楚。使用体内多光子显微镜，组织学，行为学和生物学方法，我们确定了BBB的完整性，脑血管功能障碍，淀粉样蛋白的积累，以及缺乏ADAMTS13的APPPS 1小鼠的认知障碍。我们还测试了病毒介导的ADAMTS13表达对APPPS 1小鼠脑血管功能和AD样病理学的影响。我们发现ADAMTS13缺陷导致APPPS 1小鼠早期和进行性BBB破裂以及血管密度、毛细血管灌注和脑血流量减少。我们发现ADAMTS13的缺乏增加了脑斑块负荷和A β水平，并通过阻碍BBB介导的脑A β清除而加速了脑淀粉样血管病（CAA），导致APPPS 1小鼠的认知能力下降。病毒介导的ADAMTS13表达减弱了已经显示BBB损伤和斑块沉积的APPPS 1小鼠的BBB破坏并增加了微血管、毛细血管灌注和脑血流量。这些有益的血管效应反映在脑A β清除率增加、A β脑蓄积减少和认知能力改善。我们的研究结果表明，ADAMTS13缺陷有助于AD脑血管功能障碍和由此产生的发病机制和认知缺陷，并表明ADAMTS13可能为AD提供新的治疗机会。
Blood-brain barrier (BBB) defects and cerebrovascular dysfunction contribute to amyloid-beta (A beta) brain accumulation and drive Alzheimer disease (AD) pathology. By regulating vascular functions and inflammation in the microvasculature, a disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) plays a significant protective effect in atherosclerosis and stroke. However, whether ADAMTS13 influences AD pathogenesis remains unclear. Using in vivo multiphoton microscopy, histological, behavioral, and biological methods, we determined BBB integrity, cerebrovascular dysfunction, amyloid accumulation, and cognitive impairment in APPPS1 mice lacking ADAMTS13. We also tested the impact of viral-mediated expression of ADAMTS13 on cerebrovascular function and AD-like pathology in APPPS1 mice. We show that ADAMTS13 deficiency led to an early and progressive BBB breakdown as well as reductions in vessel density, capillary perfusion, and cerebral blood flow in APPPS1 mice. We found that deficiency of ADAMTS13 increased brain plaque load and A beta levels and accelerated cerebral amyloid angiopathy (CAA) by impeding BBB-mediated clearance of brain A beta, resulting in worse cognitive decline in APPPS1 mice. Virus-mediated expression of ADAMTS13 attenuated BBB disruption and increased microvessels, capillary perfusion, and cerebral blood flow in APPPS1 mice already showing BBB damage and plaque deposition. These beneficial vascular effects were reflected by increase in clearance of cerebral A beta, reductions in A beta brain accumulation, and improvements in cognitive performance. Our results show that ADAMTS13 deficiency contributes to AD cerebrovascular dysfunction and the resulting pathogenesis and cognitive deficits and suggest that ADAMTS13 may offer novel therapeutic opportunities for AD.