Prostaglandin J2 promotes O-GlcNAcylation raising APP processing by α- and β-secretases: relevance to Alzheimer's disease

Regulation of the amyloid precursor protein (APP) processing by alpha- and beta-secretases is of special interest to Alzheimer's disease (AD), as these proteases prevent or mediate amyloid beta formation, respectively. Neuroinflammation is also implicated in AD. Our data demonstrate that the endogenous mediator of inflammation prostaglandin J2 (PGJ2) promotes full-length APP (FL-APP) processing by alpha- and beta-secretases. The decrease in FL-APP was independent of proteasomal, lysosomal, calpain, caspase, and gamma-secretase activities. Moreover, PGJ2-treatment promoted cleavage of secreted APP, specifically sAPP alpha and sAPP beta, generated by alpha and beta-secretase, respectively. Notably, PGJ2-treatment induced caspase-dependent cleavage of sAPP beta. Mechanistically, PGJ2-treatment selectively diminished mature (O- and N-glycosylated) but not immature (N-glycosylated only) FL-APP. PGJ2-treatment also increased the overall levels of protein O-GlcNAcylation, which occurs within the nucleocytoplasmic compartment. It is known that APP undergoes O-GlcNAcylation and that the latter protects proteins from proteasomal degradation. Our results suggest that by increasing protein O-GlcNAcylation levels, PGJ2 renders mature APP less prone to proteasomal degradation, thus shunting APP toward processing by alpha- and beta-secretases. (C) 2017 Elsevier Inc. All rights reserved.