title: BACE2 degradation mediated by the macroautophagy-lysosome pathway.
abstract: Neuritic plaque is the pathological hallmark in Alzheimer's disease (AD). Amyloid-β protein (Aβ), the central component of neuritic plaques, is generated from amyloid-β precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. β-site APP cleaving enzyme 2 (BACE2), a homolog of BACE1, functions differently from BACE1 in APP processing. BACE1 is the β-secretase essential for Aβ production, and BACE2, a θ-secretase, cleaves APP within the Aβ domain, preventing Aβ production. Elucidation of the mechanism underlying BACE2 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 BACE2 is approximately 20 h. Lysosomal inhibition increased BACE2 protein levels whereas proteasomal inhibition had no effect on BACE2 protein expression. Furthermore, we identified that macroautophagy mediated BACE2 degradation. Finally, we showed that lysosomal inhibition increased BACE2 cleavage of APP. Taken together, our in vitro study showed that BACE2 is degraded through the macrophagy-lysosome pathway and that lysosomal inhibition affects BACE2 processing of APP. Modulation of BACE2 degradation via the lysosomal pathway could be a new target for AD drug development.
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Xi
authors.initials: X
authors.lastname: Liu
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: Yili
authors.initials: Y
authors.lastname: Wu
authors.forename: Jianping
authors.initials: J
authors.lastname: Wang
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D016564:Amyloid beta-Protein Precursor; C509285:Bace2 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases