ADAMTS13 maintains cerebrovascular integrity to ameliorate Alzheimer-like pathology

by Yongliang Cao, Haochen Xu, Yuanbo Zhu, Mei-Juan Shi, Lixiang Wei, Jin Zhang, Shuo Cheng, Yiqian Shi, Haiyang Tong, Lijing Kang, Lu Lu, Haiyu Luo, Xing Yang, Xiaofei Bai, Ranran Wang, Yuanyuan Ma, Yun Wang, Zhongfeng Wang, Kai Zhong, Bing-Qiao Zhao, Wenying Fan Blood-brain barrier (BBB) defects and cerebrovascular dysfunction contribute to amyloid-β (Aβ) 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 mo tif, 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 dy sfunction, amyloid accumulation, and cognitive impairment inAPPPS1 mice lacking ADAMTS13. We also tested the impact of viral-mediated expression of ADAMTS13 on cerebrovascular function and AD-like pathology inAPPPS1 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 inAPPPS1 mice. We found that deficiency of ADAMTS13 increased brain plaque load and A β levels and accelerated cerebral amyloid angiopathy (CAA) by impeding BBB-mediated clearance of brain Aβ, resulting in worse cognitive decline inAPPPS1 mice. V...
Source: PLoS Biology: Archived Table of Contents - Category: Biology Authors: Source Type: research