Circulating Small Extracellular Vesicle-Derived miR-342-5p Ameliorates Beta-Amyloid Formation via Targeting Beta-site APP Cleaving Enzyme 1 in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a common neurodegenerative disorder with progressive cognitive impairment in the elderly. Beta-amyloid (Aβ) formation and its accumulation in the brain constitute one of the pathological hallmarks of AD. Until now, how to modulate Aβ formation in hippocampal neurons remains a big challenge. Herein, we investigated whether the exosomal transfer of microRNA (miR) relates to amyloid pathology in the recipient neuron cells. We isolated circulating small extracellular vesicles (sEVs) from AD patients and healthy controls, determined the miR-342-5p level in the sEVs by RT-PCR, and evaluated its diagnostic performance in AD. Then, we took advantage of biomolecular assays to estimate the role of miR-342-5p in modulating the amyloid pathway, including amyloid precursor protein (APP), beta-site APP cleaving enzyme 1 (BACE1), and Aβ42. Furthermore, we subjected HT22 cells to the sEVs from the hippocampal tissues of transgenic APP mice (Exo-APP) or C57BL/6 littermates (Exo-CTL), and the Exo-APP enriched with miR-342-5p mimics or the control to assess the effect of the sEVs’ delivery of miR-342-5p on Aβ formation. We observed a lower level of miR-342-5p in the circulating sEVs from AD patients compared with healthy controls. MiR-342-5p participated in Aβ formation by modulating BACE1 expression, specifically binding its 3′-untranslated region (UTR) sequence. Exo-APP distinctly promoted Aβ42 formation in the recipient cells compared to Exo-CTL. Intriguingly, miR-342-5p enrichment in Exo-APP ameliorated amyloid pathology in the recipient cells. Our study indicated that miR-342-5p was dysregulated in human circulating sEVs from AD patients; sEV transfer of miR-342-5p ameliorates Aβ formation by modulating BACE1 expression. These findings highlight the promising potential of exosomal miRNAs in AD clinical therapy.

Insights in RNA: 2022

“…In contrast, there were seven miRNAs (let-7d-5p, miR-384, miR-191-5p, miR-24-3p, miR-30b-5p, miR-342-3p, and miR-342-5p) that showed similar expression profiles between serum and plasma. (Kumar et al, 2013;Liu et al, 2014;Tan et al, 2014;Lugli et al, 2015;Nagaraj et al, 2017;Yang et al, 2018;Dong et al, 2022;. The miR-107 was found to be downregulated in plasma, blood, and platelet.…”

Potential Implications of miRNAs in the Pathogenesis, Diagnosis, and Therapeutics of Alzheimer’s Disease

“…MiR-374b-5p has also been verified to interact with BACE1 [157]. MiR-342-5p downregulates BACE1 expression in mouse cells, and its levels are decreased in the circulating small extracellular vesicles from patients with AD [158]. All of these miRNAs directly bind to the 3 UTR of BACE1 mRNA, suggesting that they potentially play roles in modulating Aβ pathologies (Figure 2).…”

Exosomes: A Potential Biomarker and Therapeutic Target for the Treatment of Diseases

“…Additionally, Exosome Diagnostics (US) has filed a patent [36] outlining a method for detecting neurodegenerative diseases and brain cancer (glioblastoma) through the measurement of RNAs (mRNA, miRNA, siRNA, or shRNA) associated with CSF-derived exosomes. The reported examples highlight the use of nucleic acids corresponding to APP, Aβ42, BACE1, and tau (alone or combined) as biomarkers for AD [86] and other neurodegenerative diseases, while EGFR variants were identified as potential markers for glioblastoma and other brain cancers [87].…”