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.—Tian, Y., Bustos, V., Flajolet, M., Greengard, P. A small-molecule enhancer of autophagy decreases levels of Aβ and APP-CTF via Atg5-dependent autophagy pathway.