Abstract
Neuronal miRNA dysregulation may have a role in the pathophysiology of Alzheimer’s disease (AD). miRNA(miR)-124 is largely abundant and a critical player in many neuronal functions. However, the lack of models reliably recapitulating AD pathophysiology hampers our understanding of miR-124’s role in the disease. Using the classical human SH-SY5Y-APP695 Swedish neuroblastoma cells (SH-SWE) and the PSEN1 mutant iPSC-derived neurons (iNEU-PSEN), we observed a sustained upregulation of miR-124/miR-125b/miR-21, but only miR-124 was consistently shuttled into their exosomes. The miR-124 mimic reduced APP gene expression in both AD models. While miR-124 mimic in SH-SWE neurons led to neurite outgrowth, mitochondria activation and small Aβ oligomer reduction, in iNEU-PSEN cells it diminished Tau phosphorylation, whereas miR-124 inhibitor decreased dendritic spine density. In exosomes, cellular transfection with the mimic predominantly downregulated miR-125b/miR-21/miR-146a/miR-155. The miR-124 inhibitor upregulated miR-146a in the two experimental cell models, while it led to distinct miRNA signatures in cells and exosomes. In sum, though miR-124 function may be dependent on the neuronal AD model, data indicate that keeping miR-124 level strictly controlled is crucial for proper neuronal function. Moreover, the iNEU-PSEN cellular model stands out as a useful tool for AD mechanistic studies and perhaps for the development of personalized therapeutic strategies.
Highlights
We started by confirming the elevated expression of inflammatory-associated miR-124, miR-21, miR-125b, miR-155 and miR-146a in SH-SWE cells differentiated with retinoic acid (RA) and cultured for 24 h (Figure 1A; at least p < 0.05), as we have previously shown in [15]
Given the advantage of induced pluripotent stem cell (iPSC)-derived neurons in better mimicking the Alzheimer’s disease (AD) pathophysiology [39], we evaluated whether similar changes in those inflamma-miRNAs were present in the iPSCderived iNEU-PSEN cells from the AD patient, when compared with data from the healthy iPSC-derived iNEU-WT cells
We have found that miR-124, miR-21 and miR-125b were upregulated in SH-SWE cells and their exosomes, and that increased neuronal miR-124 contributed to its increased expression levels in microglial cells, after 48 and 72 h of coculturing, leading to a decrease in the miR-124 target CCAAT/Enhancer-Binding Protein alpha (C/EBP-α) mRNA expression
Summary
By using SH-SY5Y neuroblastoma cells, An et al demonstrated that miR-124 is a potent negative regulator of β-site amyloid precursor protein-cleaving enzyme (BACE1) and that it may be involved in Alzheimer’s disease (AD) pathology, considering its reduced expression in AD sporadic patients [8]. A marked miR-124 upregulation in the hippocampus and temporal cortex was observed in AD patients and in the Tg2576 transgenic mice, where it was associated to an elevation of the amyloid-β (Aβ) peptide 1–42 [9]. These authors identified the miR-124/PTPN1 pathway as a critical mediator of synaptic dysfunction and memory loss in AD. The results about the beneficial or harmful effects of miR-124 expression levels in AD, which may result from the different models, mutations or disease stages used in such studies, are controversial
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