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ADAMTS13 maintains cerebrovascular integrity to ameliorate Alzheimer-like pathology.

Abstract：

: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 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 Aβ levels and accelerated cerebral amyloid angiopathy (CAA) by impeding BBB-mediated clearance of brain Aβ, 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 Aβ, reductions in Aβ 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.

journal_name

PLoS Biol

journal_title

PLoS biology

authors

Cao Y,Xu H,Zhu Y,Shi MJ,Wei L,Zhang J,Cheng S,Shi Y,Tong H,Kang L,Lu L,Luo H,Yang X,Bai X,Wang R,Ma Y,Wang Y,Wang Z,Zhong K,Zhao BQ,Fan W

doi

10.1371/journal.pbio.3000313

subject

Has Abstract

pub_date

2019-06-11 00:00:00

pages

e3000313

issue

eissn

1544-9173

issn

1545-7885

pii

PBIOLOGY-D-18-00021

journal_volume

pub_type

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ADAMTS13 maintains cerebrovascular integrity to ameliorate Alzheimer-like pathology.