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 assess whether our lead compound could restore Aβ-induced altered thrombosis and fibrinolysis in vivo, we examined cerebral blood flow and thrombosis in a transgenic mouse model of AD, Tg6799 mice (Oakley et al., 2006), with or without long-term treatment of RU-505. Blood flow and thrombosis were analyzed by a FeCl3-induced thrombosis model combined with intravital microscopy (Cortes-Canteli et al., 2010). We administered RU-505 or vehicle (35 mg/kg dose, every other day) to 4-mo-old Tg6799 and WT littermates for 4 mo (analyzed at 8 mo of age). Brains of 8-mo-old Tg6799 or WT mice were exposed by craniotomy, and blood flow was observed using injected fluorescence-conjugated dextran (Fig. 3 A). Three concentrations of FeCl3 (5, 10, and 15%) were incrementally administered to the brain surface to induce thrombosis. Clot formation was revealed by the appearance of an enlarging shadow superimposed on normal blood flow (Fig. 3 A and Videos 1–4). The length of all visible vessels with >20 µm diam was measured before FeCl3 treatment, and the length of occluded vessels was measured 5 min after the addition of each concentration of FeCl3 for both Tg6799 and WT. There was no significant difference in the percentage of occluded vessels before FeCl3 treatment or after 5 and 10% FeCl3 treatment among groups (Fig. 3 B). However, there was a significant difference between the percentage of occluded vessels after 15% FeCl3 treatment in vehicle-treated WT and Tg6799 mice (Fig. 3, B and C). Approximately half (52.7 ± 12.1%) of the vessels were occluded in vehicle-treated WT mice, but 95.6 ± 3.5% of vessels were occluded in vehicle-treated Tg6799 mice. RU-505 treatment significantly lowered the vessel occlusion in Tg6799 mice to 60.7 ± 8.7%, but did not change vessel occlusion in WT mice (54.2 ± 11.8%). These results suggest that our lead compound significantly restored altered thrombosis and fibrinolysis in AD mice without affecting normal thrombosis and fibrinolysis in WT littermates.
Affiliation: Laboratory of Neurobiology and Genetics and High Throughput Screening Resource Center, The Rockefeller University, New York, NY 10065.