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: CAA has been implicated in vascular degeneration of AD (Chen et al., 2006; Okamoto et al., 2010). Our previous studies showed that the Aβ–fibrinogen interaction increases Aβ fibrillization (Ahn et al., 2010). Thus, we investigated whether treatment of Tg6799 mice with RU-505 for 4 mo could decrease Aβ deposition in blood vessels. Aβ deposits were stained using Congo red, and blood vessels were labeled using laminin (green; Fig. 4 A). We quantified CAA area in the cortex by measuring Congo red deposits inside blood vessels, and Aβ plaque deposition was quantified by measuring Congo red outside blood vessels. The CAA area of RU-505–treated Tg6799 mice (0.025 ± 0.006%, cortex) was significantly decreased from that of vehicle-treated Tg6799 mice (0.046 ± 0.004%, cortex; Fig. 4 C). However, there was no significant difference in Aβ plaque area in the cortex between RU-505– and vehicle-treated Tg6799 mice (Fig. 4, B and D). WT mice did not exhibit any CAA-specific pattern of Congo red staining. This result indicates that inhibition of the Aβ–fibrinogen interaction by RU-505 reduced Aβ deposits in blood vessels of AD mice.
Affiliation: Laboratory of Neurobiology and Genetics and High Throughput Screening Resource Center, The Rockefeller University, New York, NY 10065.