Madadi et al. Cell Biosci (2019) 9:91 https://doi.org/10.1186/s13578-019-0354-3 Cell & Bioscience REVIEW Open Access Potential microRNA-related targets in clearance pathways of amyloid-β: novel therapeutic approach for the treatment of Alzheimer’s disease Soheil Madadi1, Heidi Schwarzenbach2, Massoud Saidijam3, Reza Mahjub4 and Meysam Soleimani1* Abstract Imbalance between amyloid-beta (Aβ) peptide synthesis and clearance results in Aβ deregulation. Failure to clear these peptides appears to cause the development of Alzheimer’s disease (AD). In recent years, microRNAs have become established key regulators of biological processes that relate among others to the development and progres- sion of neurodegenerative diseases, such as AD. This review article gives an overview on microRNAs that are involved in the Aβ cascade and discusses their inhibitory impact on their target mRNAs whose products participate in Aβ clear- ance. Understanding of the mechanism of microRNA in the associated signal pathways could identify novel therapeu- tic targets for the treatment of AD. Keywords: Ubiquitin–proteasome system, Autophagy, Aβ-degrading proteases, BBB transporters, Phagocytosis, Heat shock proteins, microRNAs Introduction stage, APP is cleaved to non-toxic proteins by α-secretase Alzheimer’s disease (AD)—the most common form of [6]. Aβ has two major forms: Aβ40 and Aβ42, which are dementia—is a devastating diagnosis that accounts for 40 and 42 amino acid-long fragments, respectively. Since 93,541 deaths in the United States in 2014 [1]. Clinical Aβ42 is more hydrophobic than Aβ40, it is more prone to manifestation of AD is often a loss of memory and cog- aggregate and scafold for oligomeric and fbrillar forms nitive skills. AD comprises two types: early-onset AD [7]. Te microtubule-associated protein tau regulates the (EOAD), the familial type of AD which is inherited in an assembly of microtubules and maintains its structural autosomal dominant pattern, and sporadic late-onset AD stability. Tus, it plays an important role in microtubule (LOAD), the most prevalent form of AD which develops dynamics. In AD, however, tau becomes abnormally at a later age [2]. Te main pathological characteristics in hyperphosphorylated leading to its dissociation from the brains of AD patients are extracellular senile plaques microtubules. Ten, the unbound tau molecules aggre- composed of Aβ peptides [3] and intracellular neurof- gate as insoluble flaments, which accumulate and form brillary tangles (NFTs) formed by the accumulation of neurofbrillary tangles (NFT) [8]. Te accumulation of hyperphosphorylated tau [4]. Aβ and NFTs in brain can trigger a cascade of events that Aβ is cleaved from the amyloid precursor protein may lead to AD. (APP) by β-secretase (BACE1) and γ-secretase in the According to the Aβ hypothesis, Aβ accumulation amyloidogenic pathway [5], while in the non-pathological arises from a failure of clearance rather than over-pro- duction [9]. Indeed, Bateman et al. [10] demonstrated that the clearance rate of Aβ is impaired by approximately *Correspondence: [email protected] 1 Department of Pharmaceutical Biotechnology, School of Pharmacy, 30% in the cerebrospinal fuid of patients with LOAD. Hamadan University of Medical Sciences, Hamadan, Iran Mawuenyega et al. [11] found that the clearance rate of Full list of author information is available at the end of the article Aβ40 and Aβ42 is reduced by 25% and 30%, respectively © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Madadi et al. Cell Biosci (2019) 9:91 Page 2 of 19 in AD patients. Te study by Cirrito et al. [12] showed up-regulated oncogenic miRNAs could be silenced by the efect of age on the clearance rate of Aβ and found antisense-mediated inhibition, miRNA sponges and anti- that the half-life of Aβ doubled within the interstitial miRNA peptides. As delivery vehicles of miRNAs could fuid of older animal models of AD. Tese studies def- serve polymer-based, lipid or viral vesicles or MSCs [14]. nitely established that defects in Aβ clearance have a However, to reach their destination, miRNAs (mimics fundamental role in AD pathology. Mechanisms that are or antisense) have to cross the blood–brain barrier. To involved in Aβ clearance include the ubiquitin–protea- overcome this limitation, strategies, such as the use of some system (UPS), autophagic processes, proteolytic conjugated nanoparticle or intracerebroventricular infu- enzymes, transportation across the blood brain barrier sion have been shown to improve the transport through (BBB), cellular uptake and heat shock protein (HSP)- the blood–brain barrier [15]. Further challenges for an mediated clearance, as illustrated in Fig. 1. Te relative efcient miRNA-based gene therapy are the potential contributions of each of these procedures resulting in the degradation of miRNAs by cellular nucleases and poor overall clearance of Aβ are unknown. cellular uptake. In particular, miRNAs elicit unspecifc MicroRNAs (miRNAs) have emerged as essential efects, toxicity and/or unfavorable immune response, post-transcriptional regulators of gene expression. since they only partially bind to their target mRNA. In Tese small, non-coding RNAs regulate mRNA stabil- addition, they participate in several signaling pathways ity and transcription by binding to the 3′-UTR region of and consequently, have diferent regulatory functions their targets [13]. Te dysregulation of miRNAs leads to which require further research. For example, with respect an altered protein expression which in turn results in a to the treatment of cancer, in September 2016, the spon- pathogenic signaling network connected with the imbal- soring company (Mirna Terapeutic, Inc.) stopped the ance between Aβ peptide synthesis and clearance causing enrollment and dosing of miR-34 (MRX34) in a clinical AD. Te involvement of miRNAs in these pathways may study after numerous immune-related severe adverse provide information about the molecular mechanism of efects in patients dosed with MRX34 [16]. Terefore, AD. To survey and overcome the imbalance between syn- to realize their therapeutic application, it is essential to thesis and clearing, the research feld on miRNAs may be intensely investigate the biology and functions of miR- promising, and is eligible for establishing a continuous NAs. As described above, numerous eforts have already monitoring of disease progression and therapeutic inter- made to identify miRNAs for introducing them into the ventions, not only for AD but also for other diseases. clinical practice of AD. Most notably in animal models, To date, miRNAs described above document their these miRNAs appeared to be well tolerated with prom- usefulness as diagnostic and predictive markers for AD. ising outcomes. For example, the intracerebroventricular For the assessment of miRNAs, real-time PCR, micro- infusion of anti-miR-33 inhibited the brain-specifcally arrays or even sequencing could be applied in tissues expressed miR-33 and in turn decreased Aβ levels in the and body fuids, such as plasma or serum. Te develop- cortex of mice [17]. ment of miRNA-based therapies anticipates restoring On the other hand, a disruption of miRNA biogenesis normal miRNA expression levels. In clinical settings, is to avoid since it is assumed to cause neurodegenera- the levels of down-regulated tumor suppressor miRNAs tion. For example, the onset of a neurodegenerative dis- could be normalized by their re-expression using syn- ease may happen by the loss of Dicer, an enzyme which thetic or viral vectors encoded for miRNA or synthetic cleaves pre-miRNA into a double-stranded miRNA double strand RNA molecules (mimics), whereas the duplex [18]. Such investigations show that miRNAs play an important role in long-term brain integrity and high- light their clinical relevance in AD. As up to 80% of all human genes are regulated by miRNAs [19] and their potential utility as AD biomarkers have been reported, we introduce potential miRNA-regulated targets in Aβ clearance pathways that will provide insights into the role of miRNAs in AD pathology. Ubiquitin–proteasome system Te ubiquitin–proteasome system (UPS) is the main intracellular proteolytic pathway in eukaryotic cells. Te Fig. 1 Balanced Aβ clearance pathways. UPS ubiquitin–proteasome pathway degrades more than 70–80% of intracellular pro- system, AβDPs Aβ degrading proteases, BBB blood brain barrier, HSP heat shock proteins teins, including damaged and misfolded proteins [20]. At frst, in the tagging reaction of the UPS-mediated protein Madadi et al. Cell Biosci (2019) 9:91 Page 3 of 19 degradation, a polyubiquitin chain is added to target pro- protease (MJD), otubain protease (OTU) and JAB1/ teins through three steps: (1) in an ATP-dependent pro- MPN/Mov34 metalloenzyme (JAMM) [41]. Ubiquitin cess, an ubiquitin-activating enzyme (E1) activates an C-terminal hydrolase L1 (UCHL1) appears to be the only ubiquitin (Ub) monomer, a 76-amino acid peptide; (2) the DUB playing a role in AD. It constitutes