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

ABSTRACT: 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 ?-amyloid (A?), thereby altering fibrin clot structure and delaying clot degradation. To determine if the A?-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?-fibrinogen interaction. RU-505 restored A?-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?-fibrinogen interaction show promise as therapy for treating AD.

SUBMITTER: Ahn HJ 

PROVIDER: S-EPMC4042638 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature