ADAM10 pharmacological inhibition modifies the expression of components of the dopaminergic system

Abstract

Dopamine is a primary neurotransmitter associated with memory formation, emotional control, reward processing and other higher order mental functions. Altered dopamine signaling is implied in several neuropsychiatric, neurodevelopmental and neurodegenerative disorders including Alzheimer’s disease. Age-related memory decline often presents itself with spectrum of overtly behavioral responses in patients diagnosed with Alzheimer’s disease, thus suggesting that an alteration of dopaminergic transmission could account for the psychotic symptoms observed along the pathology. Since less sAPPα production due to reduced α-secretase activity is a direct contributor of compromised neuroprotection and can impart higher vulnerability to cellular insults, we explored the impact of specific inhibition of ADAM10, the main neuronal α-secretase, on dopamine system components in cultured human SH-SY5Y neuroblastoma cells. We found that dopamine receptor D4 protein levels were dose-dependently down regulated by GI254023X, but not by the ADAM17-specific inhibitor TAPI-0. We then established that GI254023X operates at a transcriptional levels. Furthermore, we showed that GI254023X treatment also significantly increased the levels of active PKA as well as the transcription of the dopamine-degrading enzymes catechol-O-methyltransferase, monoamine oxidase A and monoamine oxidase B. Altogether, our data propose that ADAM10 inhibition modulates the dopaminergic system to possibly trigger psychosis in Alzheimer’s disease.