BACE 2 degradation mediated by the macroautophagy–lysosome pathway

Neuritic plaque is the pathological hallmark in A lzheimer's disease ( AD ). Amyloid‐β protein ( A β), the central component of neuritic plaques, is generated from amyloid‐β precursor protein ( APP ) by β‐site APP cleaving enzyme 1 ( BACE 1) and γ‐secretase. β‐site APP cleaving enzyme 2 ( BACE 2), a homolog of BACE 1, functions differently from BACE 1 in APP processing. BACE 1 is the β‐secretase essential for A β production, and BACE 2, a θ‐secretase, cleaves APP within the A β domain, preventing A β production. Elucidation of the mechanism underlying BACE 2 degradation is important for defining its biological features and its potential role in Alzheimer's disease drug development. In this report we first showed that the half‐life of BACE 2 is approximately 20 h. Lysosomal inhibition increased BACE 2 protein levels whereas proteasomal inhibition had no effect on BACE 2 protein expression. Furthermore, we identified that macroautophagy mediated BACE 2 degradation. Finally, we showed that lysosomal inhibition increased BACE 2 cleavage of APP . Taken together, our in vitro study showed that BACE 2 is degraded through the macrophagy–lysosome pathway and that lysosomal inhibition affects BACE 2 processing of APP . Modulation of BACE 2 degradation via the lysosomal pathway could be a new target for AD drug development.