Induction of Autophagy by a Novel Small Molecule Improves Aβ Pathology and Ameliorates Cognitive Deficits

Induction 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...

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Main Authors: Chu, Cheng, Zhang, Xinjiang, Ma, Wei, Li, Li, Wang, Wei, Shang, Lu, Fu, Peng
Format: Online
Language:English
Published: Public Library of Science 2013
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672196/
id pubmed-3672196
recordtype oai_dc
spelling pubmed-36721962013-06-07 Induction of Autophagy by a Novel Small Molecule Improves Aβ Pathology and Ameliorates Cognitive Deficits Chu, Cheng Zhang, Xinjiang Ma, Wei Li, Li Wang, Wei Shang, Lu Fu, Peng Research Article 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. Public Library of Science 2013-06-04 /pmc/articles/PMC3672196/ /pubmed/23750258 http://dx.doi.org/10.1371/journal.pone.0065367 Text en © 2013 Chu et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Chu, Cheng
Zhang, Xinjiang
Ma, Wei
Li, Li
Wang, Wei
Shang, Lu
Fu, Peng
spellingShingle Chu, Cheng
Zhang, Xinjiang
Ma, Wei
Li, Li
Wang, Wei
Shang, Lu
Fu, Peng
Induction of Autophagy by a Novel Small Molecule Improves Aβ Pathology and Ameliorates Cognitive Deficits
author_facet Chu, Cheng
Zhang, Xinjiang
Ma, Wei
Li, Li
Wang, Wei
Shang, Lu
Fu, Peng
author_sort Chu, Cheng
title Induction of Autophagy by a Novel Small Molecule Improves Aβ Pathology and Ameliorates Cognitive Deficits
title_short Induction of Autophagy by a Novel Small Molecule Improves Aβ Pathology and Ameliorates Cognitive Deficits
title_full Induction of Autophagy by a Novel Small Molecule Improves Aβ Pathology and Ameliorates Cognitive Deficits
title_fullStr Induction of Autophagy by a Novel Small Molecule Improves Aβ Pathology and Ameliorates Cognitive Deficits
title_full_unstemmed Induction of Autophagy by a Novel Small Molecule Improves Aβ Pathology and Ameliorates Cognitive Deficits
title_sort induction of autophagy by a novel small molecule improves aβ pathology and ameliorates cognitive deficits
description 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.
publisher Public Library of Science
publishDate 2013
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672196/
_version_ 1611983572976009216

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