microRNA 221 Targets ADAM10 mRNA and is Downregulated in Alzheimer’s Disease

Article type: Research Article

Authors: Manzine, Patricia R.^{a; *} | Pelucchi, Silvia^{d; e} | Horst, Maria A.^b | Vale, Francisco A.C.^c | Pavarini, Sofia C.I.^a | Audano, Matteo^d | Mitro, Nico^d | Di Luca, Monica^d | Marcello, Elena^d | Cominetti, Márcia R.^a

Affiliations: [a] Department of Gerontology, Federal University of São Carlos, São Carlos, SP, Brazil | [b] Faculty of Nutrition, Federal University of Goiás, Goiânia, MG, Brazil | [c] Department of Medicine, Federal University of São Carlos, São Carlos, SP, Brazil | [d] Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy | [e] Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, Università di Firenze, Florence, Italy

Correspondence: [*] Correspondence to: Patricia Regina Manzine, Laboratório de Biologia do Envelhecimento –LABEN, Departamento de Gerontologia, Universidade Federal de São Carlos, Rodovia Washington Luís, Km 235, São Carlos, SP, 13565-905, Brazil. Tel.: +55 16 3306 6672; E-mail: pmanzine@ufscar.br.

Abstract: ADAM10 is the α-secretase that cleaves amyloid-β protein precursor in the non-amyloidogenic pathway in Alzheimer’s disease (AD) and is known to be regulated by different microRNAs (miRNAs), which are post-transcriptional regulators related to several biological and pathological processes, including AD. Here we proposed to explore and validate miRNAs that have direct or indirect relations to the AD pathophysiology and ADAM10 gene. Approximately 700 miRNAs were analyzed and 21 differentially expressed miRNAs were validated in a sample of 21 AD subjects and 17 cognitively healthy matched controls. SH-SY5Y cells were transfected with miR-144-5p, miR-221, and miR-374 mimics and inhibitors, and ADAM10 protein levels were evaluated. miR-144-5p, miR-221, and miR-374 were downregulated in AD. The overexpression of miR-221 in SH-SY5Y cells resulted in ADAM10 reduction and its inhibition in ADAM10 increased. These findings show that miR-221 can be a new potential therapeutic target for increasing ADAM10 levels in AD. In addition, these results can contribute to the better understanding of ADAM10 post-transcriptional regulation.

Keywords: ADAM10 protein, aging, Alzheimer’s disease, biomarkers, microRNAs

DOI: 10.3233/JAD-170592

Journal: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 113-123, 2018