Induction of autophagy by a novel small molecule improves a? pathology and ameliorates cognitive deficits.

ABSTRACT: Growing evidence has demonstrated a neuroprotective role of autophagy in Alzheimer's disease (AD). Thus, autophagy has been regarded as a potential therapeutic target, attracting increasing interest in pharmaceutical autophagy modulation by small molecules. We designed a two-cycle screening strategy on the basis of imaging high-throughout screening (HTS) and cellular toxicity assay, and have identified a novel autophagy inducer known as GTM-1. We further showed that GTM-1 exhibits dual activities, such as autophagy induction and antagonism against A?-oligomer toxicity. GTM-1 modulates autophagy in an Akt-independent and mTOR-independent manner. In addition, we demonstrated that GTM-1 enhances autophagy clearance and reverses the downregulation of autophagy flux by thapsigargin and asparagine. Furthermore, administration of GTM-1 attenuated A? pathology and ameliorated cognitive deficits in AD mice.

SUBMITTER: Chu C 

PROVIDER: S-EPMC3672196 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature