A novel Aβ-fibrinogen interaction inhibitor rescues altered thrombosis and cognitive decline in Alzheimer's disease mice

被引：91

作者：

Ahn, Hyung Jin ^{[1
]}

Glickman, J. Fraser ^{[2
]}

Poon, Ka Lai ^{[1
]}

Zamolodchikov, Daria ^{[1
]}

Jno-Charles, Odella C. ^{[1
]}

Norris, Erin H. ^{[1
]}

Strickland, Sidney ^{[1
]}

机构：

[1] Rockefeller Univ, Lab Neurobiol & Genet, New York, NY 10065 USA

[2] Rockefeller Univ, High Throughput Screening Resource Ctr, New York, NY 10065 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2014年 / 211卷 / 06期

基金：

美国国家卫生研究院;

关键词：

CEREBRAL AMYLOID ANGIOPATHY; TRANSGENIC MICE; BLOOD-VESSELS; RISK-FACTORS; DEMENTIA; DEPOSITION; PROTEIN; BRAIN; PATHOLOGY; APP;

D O I：

10.1084/jem.20131751

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Many Alzheimer's disease (AD) patients suffer from cerebrovascular abnormalities such as altered cerebral blood flow and cerebral microinfarcts. Recently, fibrinogen has been identified as a strong cerebrovascular risk factor in AD, as it specifically binds to beta-amyloid (A.), thereby altering fibrin clot structure and delaying clot degradation. To determine if the A beta-fibrinogen interaction could be targeted as a potential new treatment for AD, we designed a high-throughput screen and identified RU-505 as an effective inhibitor of the A beta-fibrinogen interaction. RU-505 restored A beta-induced altered fibrin clot formation and degradation in vitro and inhibited vessel occlusion in AD transgenic mice. Furthermore, long-term treatment of RU-505 significantly reduced vascular amyloid deposition and microgliosis in the cortex and improved cognitive impairment in mouse models of AD. Our studies suggest that inhibitors targeting the A beta-fibrinogen interaction show promise as therapy for treating AD.

引用

页码：1049 / 1062

页数：14

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