Methamphetamine regulates βAPP processing in human neuroblastoma cells

• Published in: Neuroscience letters 2019-05, Vol.701, p.20-25
• Main Authors: Shukla, Mayuri, Maitra, Subhamita, Hernandez, Jean-François, Govitrapong, Piyarat, Vincent, Bruno
• Format: Article
• Language: English
• Subjects: ADAM10 Protein - metabolism; Alzheimer’s disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - metabolism; Cell Line, Tumor; Chemical Sciences; Drug abuse; Humans; Medicinal Chemistry; Metabolism; Methamphetamine; Methamphetamine - pharmacology; Neuroblastoma; Secretase; βAPP
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2019.02.023

•Meth at 1 and 10μM increased the production of sAPPα metabolite in human SH-SY5Y cells.•Meth at 1 and 10μM stimulated the expression and the catalytic activity of the main α-secretase ADAM10.•Meth at higher doses (100μM and 1 mM) did not interfere with sAPPα production and ADAM10 biology.•Meth dose-dependently increases the expression and the catalytic activity of the β-secretase BACE1.•Meth-dependent regulations of secretases unveiled how the drug can convey pro-AD or therapeutic effects depending on the doses used. Methamphetamine is a potent and highly addictive psychostimulant whose abuse has turned out to be a global health hazard. The multitudinous effects it exerts at the cellular level induces neurotoxic responses in the human brain, ultimately leading to neurocognitive disorders. Strikingly, brain changes, tissue damage and neuropsychological symptoms due to Meth exposure compels and necessitates to link the probability of risk of developing premature Alzheimer’s disease, a progressive neurodegenerative disorder characterized by amyloid plaques composed of amyloid-β peptides and clinical dementia. These peptides are derived from sequential cleavages of the β-amyloid precursor protein by β- and γ-secretases. Previous studies reveals evidence for both positive and negative effects of Meth pertaining to cognitive functioning based on the dosage paradigm and duration of exposure revealing a beneficial psychotropic profile under some conditions and deleterious cognitive deficits under some others. In this context, we proposed to examine the effect of Meth on βAPP metabolism and βAPP-cleaving secretases in the human neuroblastoma SH-SY5Y cell line. Our results showed that Meth dose-dependently increases BACE1 expression and catalytic activity, while its effect on the α-cleavage of βAPP and on the expression and catalytic activity of the main α-secretase ADAM10 display a bell-curve shape. To our knowledge, the present study is the first to demonstrate that Meth can control βAPP-cleaving secretases. Moreover, we propose from these findings that the deleterious effect of Meth on cognitive decline might be an outcome of high dosage paradigm whereas acute and short-term drug use which stimulated sAPPα might produce improvements in cognition in disorders such as AD.