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Research and Publications - Department of Biological Sciences

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Browsing Research and Publications - Department of Biological Sciences by Subject "A-BETA-40"

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    Clioquinol promotes the degradation of metal-dependent amyloid-beta (A beta) oligomers to restore endocytosis and ameliorate A beta toxicity
    (National Academy of the Sciences, 2014) Matlack, Kent E. S.; Tardiff, Daniel F.; Narayan, Priyanka; Hamamichi, Shusei; Caldwell, Kim A.; Caldwell, Guy A.; Lindquist, Susan; Massachusetts Institute of Technology (MIT); Whitehead Institute; University of Alabama Tuscaloosa; Howard Hughes Medical Institute
    Alzheimer's disease (AD) is a common, progressive neurodegenerative disorder without effective disease-modifying therapies. The accumulation of amyloid-beta peptide (A beta) is associated with AD. However, identifying new compounds that antagonize the underlying cellular pathologies caused by A beta has been hindered by a lack of cellular models amenable to high-throughput chemical screening. To address this gap, we use a robust and scalable yeast model of A beta toxicity where the A beta peptide transits through the secretory and endocytic compartments as it does in neurons. The pathogenic A beta 1-42 peptide forms more oligomers and is more toxic than A beta 1-40 and genome-wide genetic screens identified genes that are known risk factors for AD. Here, we report an unbiased screen of similar to 140,000 compounds for rescue of A beta toxicity. Of similar to 30 hits, several were 8-hydroxyquinolines (8-OHQs). Clioquinol (CQ), an 8-OHQ previously reported to reduce A beta burden, restore metal homeostasis, and improve cognition in mouse AD models, was also effective and rescued the toxicity of A beta secreted from glutamatergic neurons in Caenorhabditis elegans. In yeast, CQ dramatically reduced A beta peptide levels in a copper-dependent manner by increasing degradation, ultimately restoring endocytic function. This mirrored its effects on copper-dependent oligomer formation in vitro, which was also reversed by CQ. This unbiased screen indicates that copper-dependent A beta oligomer formation contributes to A beta toxicity within the secretory/endosomal pathways where it can be targeted with selective metal binding compounds. Establishing the ability of the A beta yeast model to identify disease-relevant compounds supports its further exploitation as a validated early discovery platform.