Pin1 Regulatory miRNAs as Novel Candidates for Alzheimer’s Disease Treatment

Abstract

Alzheimers disease (AD) is the sixth leading cause of death in elderly people whose pathological hallmarks include senile plaques and neurofibrillary tangles (NFTs). The tangles are composed of hyperphosphorylated tau, which is a microtubule-associated protein and its hyperphosphorylation would result in its aggregation and neural cell death. Recently, it has been shown that phosphorylated tau at Thr231 exists in two distinct cis & trans conformations, whose conversion is being mediated by Pin1 isomerase and that the cis, but not the trans, is extremely neurotoxic and drives tau hyperphosphorylation. It has been demonstrated that Pin1 inhibition reflects cis pT231-tau accumulation in neurons but its overactivation is observed in cancer stem cells. Hence, a precise Pin1 regulation is required to keep cells in healthy conditions. As miRNAs play a crucial role in fine-tuning of the gene-expression level, we hypothesized that they might regulate the Pin1 dosage. Nonetheless, the possible regulatory roles of miRNAs in progression of AD by regulating PIN1 is not well studied. We aimed to identify potential miRNAs that down-regulate PIN1 in AD. This can uncover new regulatory mechanisms that result in AD. Thus, we performed a comprehensive study of miRNAs, capable in regulating Pin1, through whole-genome meta-analysis by integrating miRNA expression profiles of 846 different biological samples, along with a systematic literature review and data mining of multiple experimental and predicted miRNA-target databases. We created a list of 56 candidates, which was then short-listed to 10 miRNAs with vigorous experimental evidence. We examined the expression patterns of these miRNAs in the AD and healthy controls and integrated mRNA and miRNA expression profiles to study possible interactions between miRNAs and Pin1. Moreover, we performed an in-silico functional analysis by integrating data of knock-in and knock-down experiments of the candidate miRNAs, and highlighted miR296-5p, miR200b, miR200c, miR140-5p, and miR874 as strong candidate Pin1 regulators. These findings would have profound implications in developing novel therapeutic strategies for AD by blocking expression of highlighted miRNAs using antagomirs.