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

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 EC50 of ∼10 μM) and APP-CTF (apparent EC50 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 effe...