In:
PLOS Biology, Public Library of Science (PLoS), Vol. 17, No. 6 ( 2019-6-11), p. e3000313-
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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3000313
DOI:
10.1371/journal.pbio.3000313.g001
DOI:
10.1371/journal.pbio.3000313.g002
DOI:
10.1371/journal.pbio.3000313.g003
DOI:
10.1371/journal.pbio.3000313.g004
DOI:
10.1371/journal.pbio.3000313.g005
DOI:
10.1371/journal.pbio.3000313.g006
DOI:
10.1371/journal.pbio.3000313.g007
DOI:
10.1371/journal.pbio.3000313.s001
DOI:
10.1371/journal.pbio.3000313.s002
DOI:
10.1371/journal.pbio.3000313.s003
DOI:
10.1371/journal.pbio.3000313.s004
DOI:
10.1371/journal.pbio.3000313.s005
DOI:
10.1371/journal.pbio.3000313.s006
DOI:
10.1371/journal.pbio.3000313.s007
DOI:
10.1371/journal.pbio.3000313.s008
DOI:
10.1371/journal.pbio.3000313.s009
DOI:
10.1371/journal.pbio.3000313.s010
DOI:
10.1371/journal.pbio.3000313.s011
DOI:
10.1371/journal.pbio.3000313.s012
DOI:
10.1371/journal.pbio.3000313.s013
DOI:
10.1371/journal.pbio.3000313.s014
DOI:
10.1371/journal.pbio.3000313.s015
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2019
detail.hit.zdb_id:
2126773-X
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