MicroRNA-144 Is Regulated by Activator Protein-1 (AP-1) and Decreases Expression of Alzheimer’s Disease-related A Disintegrin And Metalloprotease 10 (ADAM10)

Background: MicroRNA (miR) dysregulation is found in Alzheimer's disease (AD). A disintegrin and metalloprotease 10 (ADAM10) prevents generation of amyloid β (Aβ) and decrease AD pathology. Results: miR-144 suppresses ADAM10 expression and is up-regulated by activator protein-1. Conclusion: miR-144 is negative regulator of ADAM10 and may be involved in AD pathogenesis. Significance: The first work to demonstrate the function of miRNA-144 and its regulation in the pathogenesis of AD. SUMMARY Amyloid β-peptide (Aβ) accumulating in the brain of Alzheimer’s disease (AD) patients is believed to be the main pathophysiologcal cause of the disease. Proteolytic processing of the amyloid precursor protein by α-secretase ADAM10 (a disintegrin and metalloprotease 10) protects the brain from the production of the Aβ. Meanwhile, Dysregulation or aberrant expression of microRNAs (miRNAs) has been widely documented in AD patients. In this study, we demonstrated that over-expression of miR-144, which was previously reported to be increased in elderly primate brains and in AD patients, significantly decreased activity of the luciferase reporter containing the ADAM10 3’-untranslated region (3’-UTR) and suppressed ADAM10 protein level, whereas miR-144 inhibitor led to an increase of the luciferase activity and the protein. The negative regulation caused by miR-144 was strictly dependent on the binding of the miRNA to its recognition element in the ADAM10 3’-UTR. Moreover, we also showed that Activator protein-1 regulates the transcription of miR-144 and the up-regulation of miR-144 at least partially induces the suppression of the ADAM10 protein in the presence of Aβ. In addition, we found that miR-451, a miRNA processed from a single gene locus with miR-144, is also involved in the regulation of ADAM10 expression. Taken together, our data therefore demonstrate miR-144/451 is negative regulators of ADAM10 protein and suggest a mechanistic role for miR-144/451 in AD pathogenesis. Alzheimer’s disease (AD) is a neurodegenerative disease that accounts for 50 to 60% of dementia cases in the elderly (1). The amyloid β-peptide (Αβ) is believed to be the essential cause of AD pathology and is produced by sequential proteolytic cleavages of the http://www.jbc.org/cgi/doi/10.1074/jbc.M112.381392 The latest version is at JBC Papers in Press. Published on April 1, 2013 as Manuscript M112.381392