biostudies-literatureUnknown8(6)Chu CGrowing 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 Aβ-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 Aβ pathology and ameliorated cognitive deficits in AD mice.PloS onee65367https://www.ebi.ac.uk/biostudies/studies/S-EPMC3672196biostudies-literatureInduction of autophagy by a novel small molecule improves aβ pathology and ameliorates cognitive deficits.PMC3672196Chu CShang LZhang XWang WLi LFu PMa WfalseInduction of autophagy by a novel small molecule improves aβ pathology and ameliorates cognitive deficits.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 Aβ-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 Aβ pathology and ameliorated cognitive deficits in AD mice.2013-01-01T00:00:00Z20132024-11-05T20:54:26.387Z2019-03-26T23:14:38ZS-EPMC36721962375025810.1371/journal.pone.0065367