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

Abstract

In Alzheimer's disease (AD), damaged Aβ clearance contributes to elevated levels of Aβ that cause a series of cytotoxic cascade reactions. Thus, targeting Aβ clearance has now been considered a valid therapeutic approach for AD. Cellular uptake and degradation are important mechanisms for Aβ 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 Aβ 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 Aβ 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 Aβ accumulation in lysosomes was observed in OAB-14-treated AD mice. These results suggest that OAB-14 may promote Aβ clearance in lysosomes by alleviating the EAL dysfunction in AD mice.