Methamphetamine regulates βAPP processing in human neuroblastoma cells

NEUROSCIENCE LETTERS

卷:701

Article

Shukla, Mayuri^1,2,3  Maitra, Subhamita¹  Hernandez, Jean-Francois⁴  Govitrapong, Piyarat^1,2,3  Vincent, Bruno^1,5 

[1] Mahidol Univ, Inst Mol Biosci, Salaya 73170, Nakhon Pathom, Thailand

[2] Mahidol Univ, Res Ctr Neurosci, Salaya 73170, Nakhon Pathom, Thailand

[3] Chulabhorn Royal Acad, Chulabhorn Grad Inst, Bangkok 10210, Thailand

[4] Univ Montpellier, CNRS, UMR5247, Inst Biomol Max Mousseron,ENSCM,Fac Pharm, F-34093 Montpellier 5, France

[5] CNRS, 2 Rue Michel Ange, F-75016 Paris, France

关键词: Alzheimer's disease;    Methamphetamine;    Drug abuse;    beta APP;    Secretase;    Metabolism;   

DOI  :  10.1016/j.neulet.2019.02.023

来源: Elsevier

【 摘 要 】

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-beta peptides and clinical dementia. These peptides are derived from sequential cleavages of the beta-amyloid precursor protein by beta- and gamma-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 beta APP metabolism and beta APP-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 a-cleavage of beta APP and on the expression and catalytic activity of the main alpha-secretase ADAM10 display a bell-curve shape. To our knowledge, the present study is the first to demonstrate that Meth can control beta APP-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 sAPP alpha might produce improvements in cognition in disorders such as AD.

【 授权许可】

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