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 investigate this idea, we designed a high-throughput screen (HTS) to identify small molecules that inhibit the interaction between Aβ and fibrinogen. Low molecular weight compounds were screened using fluorescence polarization (FP) and AlphaLISA assays in a complementary fashion to cross check the activity of the hit compounds and to ensure the removal of false-positive artifacts. Primarily, ∼93,000 compounds were screened using FP, which measured the changes in the anisotrophy induced by binding of a 5-carboxy-tetramethylrhodamine (TAMRA)–labeled Aβ peptide to fibrinogen (Fig. 1 A). Then, hits from FP were screened using AlphaLISA to independently confirm the activity of the inhibitors identified in the FP assay (Fig. 1 B). After both steps, we selected only drug-like compounds using Lipinski’s Rule of Five, which allowed us to determine which chemical compounds have pharmacological properties that would make them likely orally active drugs in humans (Lipinski et al., 2001). We also filtered out artifactual compounds using a quenching assay, which identifies insoluble compounds, singlet oxygen quenchers, and biotin mimetics interfering with the AlphaLISA signal. We identified several candidate compounds with half-maximal inhibitions (IC50) between 10 and 50 µM from the dose-response assays using both FP and AlphaLISA assays (Table 1).
Affiliation: Laboratory of Neurobiology and Genetics and High Throughput Screening Resource Center, The Rockefeller University, New York, NY 10065.