Neuronal Dynamics and miRNA Signaling Differ between SH-SY5Y APPSwe and PSEN1 Mutant iPSC-Derived AD Models upon Modulation with miR-124 Mimic and Inhibitor

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http://hdl.handle.net/10138/334602

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Garcia, G.; Pinto, S.; Cunha, M.; Fernandes, A.; Koistinaho, J.; Brites, D. Neuronal Dynamics and miRNA Signaling Differ between SH-SY5Y APPSwe and PSEN1 Mutant iPSC-Derived AD Models upon Modulation with miR-124 Mimic and Inhibitor. Cells 2021, 10, 2424.

Julkaisun nimi: Neuronal Dynamics and miRNA Signaling Differ between SH-SY5Y APPSwe and PSEN1 Mutant iPSC-Derived AD Models upon Modulation with miR-124 Mimic and Inhibitor
Tekijä: Garcia, Gonçalo; Pinto, Sara; Cunha, Mar; Fernandes, Adelaide; Koistinaho, Jari; Brites, Dora
Julkaisija: Multidisciplinary Digital Publishing Institute
Päiväys: 2021-09-14
URI: http://hdl.handle.net/10138/334602
Tiivistelmä: 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-<i>APP695 Swedish</i> neuroblastoma cells (SH-<i>SWE</i>) and the <i>PSEN1</i> mutant iPSC-derived neurons (iNEU-<i>PSEN</i>), 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 <i>APP</i> gene expression in both AD models. While miR-124 mimic in SH-<i>SWE</i> neurons led to neurite outgrowth, mitochondria activation and small Aβ oligomer reduction, in iNEU-<i>PSEN</i> 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-<i>PSEN</i> cellular model stands out as a useful tool for AD mechanistic studies and perhaps for the development of personalized therapeutic strategies.


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