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

作者：Tian Yuan; Bustos Victor; Flajolet Marc^*; Greengard Paul

来源：The FASEB Journal, 2011, 25(6): 1934-1942.

DOI：10.1096/fj.10-175158

• Alzheimer's disease
• SMER28
• Beclin1
• Ulk1

The hallmarks of Alzheimer's disease are the aggregates of amyloid-beta (A beta) 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 A beta 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 A beta peptide (apparent EC(50) of similar to 10 mu M) and APP-CTF (apparent EC50 of similar to 20 mu M) in a gamma-secretase-independent manner. Pharmacological inhibition of autophagy led to a significant accumulation of A beta 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 A beta 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 A beta 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.-Tian, Y., Bustos, V., Flajolet, M., Greengard, P. A small-molecule enhancer of autophagy decreases levels of A beta and APP-CTF via Atg5-dependent autophagy pathway. FASEB J. 25, 1934-1942 (2011). www.fasebj.org

• 出版日期2011-6