OAB-14 Effectively Ameliorates the Dysfunction of the Endosomal-Autophagic-Lysosomal Pathway in APP/PS1 Transgenic Mice

In Alzheimer's disease (AD), damaged A beta clearance contributes to elevated levels of A beta that cause a series of cytotoxic cascade reactions. Thus, targeting A beta clearance has now been considered a valid therapeutic approach for AD. Cellular uptake and degradation are important mechanisms for A beta clearance, which are mainly performed by the endosomal-autophagic-lysosomal (EAL) pathway. Our previous study showed that OAB-14, a novel small molecule designed with bexarotene as the lead compound, treatment for 3 months significantly alleviated cognitive disorders and remarkably reduced the deposition of A beta without affecting its production in APP/PS1 transgenic mice. Here, we further revealed that enhancement of the EAL activity is one of the mechanisms that increases A beta clearance after OAB-14 administration for 3 months. OAB-14 facilitates receptor-mediated endocytosis and restores autophagy flux via the AMPK/mTOR pathway. Meanwhile, OAB-14 enhances the lysosomal activity, and reduced A beta accumulation in lysosomes was observed in OAB-14-treated AD mice. These results suggest that OAB-14 may promote A beta clearance in lysosomes by alleviating the EAL dysfunction in AD mice.