Clioquinol promotes the degradation of metal-dependent amyloid-? (A?) oligomers to restore endocytosis and ameliorate A? toxicity.

ABSTRACT: Alzheimer's disease (AD) is a common, progressive neurodegenerative disorder without effective disease-modifying therapies. The accumulation of amyloid-? peptide (A?) is associated with AD. However, identifying new compounds that antagonize the underlying cellular pathologies caused by A? 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? toxicity where the A? peptide transits through the secretory and endocytic compartments as it does in neurons. The pathogenic A? 1-42 peptide forms more oligomers and is more toxic than A? 1-40 and genome-wide genetic screens identified genes that are known risk factors for AD. Here, we report an unbiased screen of ?140,000 compounds for rescue of A? toxicity. Of ?30 hits, several were 8-hydroxyquinolines (8-OHQs). Clioquinol (CQ), an 8-OHQ previously reported to reduce A? burden, restore metal homeostasis, and improve cognition in mouse AD models, was also effective and rescued the toxicity of A? secreted from glutamatergic neurons in Caenorhabditis elegans. In yeast, CQ dramatically reduced A? 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? oligomer formation contributes to A? toxicity within the secretory/endosomal pathways where it can be targeted with selective metal binding compounds. Establishing the ability of the A? yeast model to identify disease-relevant compounds supports its further exploitation as a validated early discovery platform.

SUBMITTER: Matlack KE 

PROVIDER: S-EPMC3964050 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature