ADAMTS13 maintains cerebrovascular integrity to ameliorate Alzheimer-like pathology.
PLoS Biol
; 17(6): e3000313, 2019 06.
Article
em En
| MEDLINE
| ID: mdl-31185010
ABSTRACT
Blood-brain barrier (BBB) defects and cerebrovascular dysfunction contribute to amyloid-ß (Aß) 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 Aß levels and accelerated cerebral amyloid angiopathy (CAA) by impeding BBB-mediated clearance of brain Aß, 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 Aß, reductions in Aß 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Circulação Cerebrovascular
/
Proteína ADAMTS13
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
PLoS Biol
Assunto da revista:
BIOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
China