A novel Aβ-fibrinogen interaction inhibitor rescues altered thrombosis and cognitive decline in Alzheimer's disease mice.
Bottom Line: To determine if the Aβ-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 Aβ-fibrinogen interaction.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 Aβ-fibrinogen interaction show promise as therapy for treating AD.
Affiliation: Laboratory of Neurobiology and Genetics and High Throughput Screening Resource Center, The Rockefeller University, New York, NY 10065.Show MeSH
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Mentions: Because RU-505 restored Aβ-induced altered thrombosis and impaired fibrinolysis in vitro and in vivo, we explored whether long-term RU-505 treatment could have behavioral effects on AD mice. 7-mo-old Tg6799 mice treated for 3 mo with RU-505 were tested using contextual fear conditioning to assess possible cognitive changes. RU-505 treatment had no effect on baseline freezing behavior in WT and Tg6799 mice (Fig. 5 A). When we evaluated contextual memory of Tg6799 and WT mice 24 h after training, vehicle-treated Tg6799 mice showed a severe memory deficit compared with vehicle-treated WT mice (Fig. 5 B). RU-505–treated Tg6799 mice exhibited significantly improved memory compared with their vehicle-treated AD counterparts, whereas long-term treatment of RU-505 in WT mice did not impact basal freezing behavior or contextual memory.
Affiliation: Laboratory of Neurobiology and Genetics and High Throughput Screening Resource Center, The Rockefeller University, New York, NY 10065.