PLoS ONE (Jan 2013)

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

  • Cheng Chu,
  • Xinjiang Zhang,
  • Wei Ma,
  • Li Li,
  • Wei Wang,
  • Lu Shang,
  • Peng Fu

DOI
https://doi.org/10.1371/journal.pone.0065367
Journal volume & issue
Vol. 8, no. 6
p. e65367

Abstract

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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.