[摘要]：Agonist-induced activation of the delta-opioid receptor (delta OR) was recently shown to augment beta- and gamma-secretase activities, which increased the production of beta-amyloid peptide (A beta), known to accumulate in the brain tissues of Alzheimer's disease (AD) patients. Previously, the delta OR variant with a phenylalanine at position 27 (delta OR-Phe27) exhibited more efficient receptor maturation and higher stability at the cell surface than did the less common cysteine (delta OR-Cys27) variant. For this study, we expressed these variants in human SH-SY5Y and HEK293 cells expressing exogenous or endogenous amyloid precursor protein (APP) and assessed the effects on APP processing. Expression of delta OR-Cys27, but not delta OR-Phe27, resulted in a robust accumulation of the APP C83 C-terminal fragment and the APP intracellular domain, while the total soluble APP and, particularly, the beta-amyloid 40 levels were decreased. These changes upon delta OR-Cys27 expression coincided with decreased localization of APP C-terminal fragments in late endosomes and lysosomes. Importantly, a long-term treatment with a subset of delta OR-specific ligands or a c-Src tyrosine kinase inhibitor suppressed the delta OR-Cys27-induced APP phenotype. These data suggest that an increased constitutive internalization and/or concurrent signaling of the delta OR-Cys27 variant affects APP processing through altered endocytic trafficking of APP.
