Drug discovery in Alzheimer’s disease using metal chelators: Warning toward their usage

Alzheimer’s disease (AD) is a devastating neurodegenerative dementia exhibiting abnormal protein aggregations of amyloid β and tau proteins in the brain. Although its detailed molecular mechanism remains unclear, accumulating evidences have suggested that autophagy is impaired in AD patients. Autophagy is a fundamental degradation process to clear unnecessary and even pathological substances in the cells, functioning a key cellular process for homeostasis. Recent attempts employing metal chelators such as clioquinol for the treatment of AD have been made because Aβ and tau protein can bind to metal ions such as copper and zinc and their contents are known to be abnormal in AD. By chelating these metals with chelators, protein aggregates can be dissolved resulting in the clearance of aggregated proteins. Recent studies, however, have suggested that clioquinol can induce autophagy and can cause autophagy-related cell death depending on its concentration. Therefore, we should be very careful for its concentration in vivo when it is used for the treatment of AD.