Constructing and characterizing a bioactive small molecule and microRNA association network for Alzheimer's disease

Abstract

Alzheimer's disease (AD) is an incurable neurodegenerative disorder. Much effort has been devoted to developing effective therapeutic agents. Recently, targeting microRNAs (miRNAs) with small molecules has become a novel therapy for human diseases. In this study, we present a systematic computational approach to construct a bioactive Small molecule and miRNA association Network in AD (SmiRN-AD), which is based on the gene expression signatures of bioactive small molecule perturbation and AD-related miRNA regulation. We also performed topological and functional analysis of the SmiRN-AD from multiple perspectives. At the significance level of p ≤ 0.01, 496 small molecule–miRNA associations, including 25 AD-related miRNAs and 275 small molecules, were recognized and used to construct the SmiRN-AD. The drugs that were connected with the same miRNA tended to share common drug targets ( p = 1.72 × 10 −4 ) and belong to the same therapeutic category ( p = 4.22 × 10 −8 ). The miRNAs that were linked to the same small molecule regulated more common miRNA targets ( p = 6.07 × 10 −3 ). Further analysis of the positive connections (quinostatin and miR-148b, amantadine and miR-15a) and the negative connections (melatonin and miR-30e-5p) indicated that our large-scale predictions afforded specific biological insights into AD pathogenesis and therapy. This study proposes a holistic strategy for deciphering the associations between small molecules and miRNAs in AD, which may be helpful for developing a novel effective miRNA-associated therapeutic strategy for AD. A comprehensive database for the SmiRN-AD and the differential expression patterns of the miRNA targets in AD is freely available at http://bioinfo.hrbmu.edu.cn/SmiRN-AD/ .

Identification of associations between small molecule drugs and miRNAs based on functional similarity

“…First, we computed the Meet/Min score for each pair of miRNAs to evaluate the extent of shared target genes [15, 16]. The Meet/min score between two miRNAs was defined as the number of common target genes of two miRNAs divided by the small number of target genes of the two miRNAs.…”

“…Besides the structure based method, Jiang et al proposed a novel method to construct small molecule-miRNA networks for 23 different cancers based on the similarity of transcriptional responses [15]. Similar work has also been done for Alzheimer's disease [16]. However, since lack of miRNA-transfected datasets, we simulated the transcriptional responses of miRNA perturbation through intersecting target genes and differential expressed genes of specific disease.…”

Pathogenetic and therapeutic applications of microRNAs in major depressive disorder

“…Thus, there are many strategies that can be used to inhibit or overexpress miRNA of interest. Several of these strategies are in pipeline for neurodegenerative diseases (Meng et al, 2013) but it will be interesting to see if these methods/strategies are useful in the complex disorders such as MDD.…”

The recent development in synthesis and pharmacological evaluation of small molecule to treat Alzheimer's diseases: A review

“…Further analysis of the positive connections (quinostatin and miR-148b, amantadine and miR-15a) and the negative connections (melatonin and miR-30e-5p) indicated that our large-scale predictions afforded specific biological insights into AD pathogenesis and therapy. This study proposes a holistic strategy for deciphering the associations between small molecules and miRNAs in AD, which may be helpful for developing a novel effective miRNA-associated therapeutic strategy for AD (Meng et al, 2014). Augmenting BDNF/TrkB signaling has been demonstrated to be a promising strategy for reversing cognitive deficits in preclinical models of Alzheimer disease (AD).…”