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

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.