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

摘要

Amyloid β-peptide (Aβ) accumulating in the brain of Alzheimer 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 overexpression of miR-144, which was previously reported to be increased in elderly primate brains and AD patients, significantly decreased activity of the luciferase reporter containing the ADAM10 3′-untranslated region (3′-UTR) and suppressed the ADAM10 protein level, whereas the miR-144 inhibitor led to an increase of the luciferase activity. 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 a negative regulator of the ADAM10 protein and suggest a mechanistic role for miR-144/451 in AD pathogenesis.