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: To further address any possible issue of hypoactivity in the Tg6799 mice and to test whether RU-505 treatment had a similar effect on a different strain of AD transgenic mice, we administered RU-505 to 4-mo-old TgCRND8 mice (Chishti et al., 2001) for 3 mo (analyzed at 7 mo-of-age) as a pilot experiment. During training, RU-505 treatment did not lead to improvement in spatial learning in TgCRND8 mice (Fig. 6 A); however, this treatment significantly reduced the latency to reach the target hole during the probe trial compared with vehicle-treated TgCRND8 mice (Fig. 6 B). Furthermore, the number of visits to the target hole during the probe trial was significantly higher in RU-505–treated TgCRND8 mice compared with vehicle-treated TgCRND8 mice (Fig. 6 C). In addition, vehicle-treated TgCRND8 mice showed similar locomotor activity during probe trials (Fig. 6 D), indicating that the impaired performance of vehicle-treated TgCRND8 mice in Barnes maze test is more likely caused by deficits in spatial memory. These results suggest that treatment of RU-505 substantially improved the deficits in spatial memory of TgCRND8 mice.
Affiliation: Laboratory of Neurobiology and Genetics and High Throughput Screening Resource Center, The Rockefeller University, New York, NY 10065.