Dopamine promotes cathepsin B-mediated amyloid precursor protein degradation by reactive oxygen species-sensitive mechanism in neuronal cell.

Recent literature suggested an important function of native amyloid precursor protein (APP) as amine oxidase implicating in protection of brain cells from catecholamine-induced toxicity. However, any role of catecholamines on regulation of native APP has not been explored. Here we report that dopamine (DA), one of the most prominent catecholamine neurotransmitters in brain, down-modulates native APP protein in several neuronal cell types. Using SH-SY5Y cells as model, we detected no alteration of transcript expression and unaffected translation suggested that DA might induce APP degradation. We actually found that DA treatment decreased the stability of APP. Lysosomal blockers inhibited DA-induced APP degradation, but specific proteasomal blocker failed to do so. We detected the role of cathepsin B in DA-induced APP degradation by using pharmacological inhibitor and specific siRNA. We also revealed that DA could increase cathepsin B expression at both transcript and protein levels. Using antioxidant N-acetyl cysteine, we detected increased level of reactive oxygen species generation that was found responsible for induced cathepsin B expression by DA and resultant APP degradation. Our study reveals the existence of reciprocal regulation of a catecholamine and an amine oxidase implicating in brain catecholamine homeostasis.