1. Academic Validation
  2. A small-molecule enhancer of autophagy decreases levels of Abeta and APP-CTF via Atg5-dependent autophagy pathway

A small-molecule enhancer of autophagy decreases levels of Abeta and APP-CTF via Atg5-dependent autophagy pathway

  • FASEB J. 2011 Jun;25(6):1934-42. doi: 10.1096/fj.10-175158.
Yuan Tian 1 Victor Bustos Marc Flajolet Paul Greengard
Affiliations

Affiliation

  • 1 Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, 1230 York Ave., New York, NY 10065, USA.
Abstract

The hallmarks of Alzheimer's disease are the aggregates of Amyloid-β (Αβ) peptide and Tau Protein. Autophagy is one major cellular pathway leading to the removal of aggregated proteins. We examined the possibility of inducing Autophagy to reduce Aβ peptide and the amyloid precursor protein (APP)-derived fragment APP-CTF levels in cell lines and primary neuronal cultures. We found that induction of Autophagy either by small-molecule enhancers of rapamycin (SMER)28, a small-molecule enhancer of Autophagy, or following starvation greatly decreased the levels of Aβ peptide (apparent EC(50) of ∼10 μM) and APP-CTF (apparent EC(50) of ∼20 μM) in a γ-secretase-independent manner. Pharmacological inhibition of Autophagy led to a significant accumulation of Aβ peptide and APP-CTF and diminished the effect of SMER28. Three essential components of the autophagic pathway, autophagy-related protein (Atg)5, Beclin1, and ULK1, were shown to be involved in the degradation of Aβ and APP-CTF, and Atg5 was necessary for the effect of SMER28. In addition, the autophagic marker LIGHT chain 3-II cocompartmentalized with APP-CTF. These results support the involvement of Autophagy in the clearance of Aβ and APP-CTF. We therefore propose that small molecule enhancers of Autophagy, such as SMER28, may have therapeutic potential for the treatment of Alzheimer's disease and other proteinopathies.

Figures
Products
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    Product Name
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  • HY-100200
    99.92%, Autophagy Positive Regulator