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

Alzheimer's disease (AD) is a common neurodegenerative disorder with progressive cognitive impairment in the elderly. Beta-amyloid (A beta) formation and its accumulation in the brain constitute one of the pathological hallmarks of AD. Until now, how to modulate A beta 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 A beta 42. 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 A beta 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 A beta formation by modulating BACE1 expression, specifically binding its 3 '-untranslated region (UTR) sequence. Exo-APP distinctly promoted A beta 42 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 A beta formation by modulating BACE1 expression. These findings highlight the promising potential of exosomal miRNAs in AD clinical therapy.

Automated summary

Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of beta-amyloid (Aβ) in the brain. This study found that the level of miR-342-5p was decreased in circulating small extracellular vesicles from Alzheimer's disease patients compared to healthy controls, and miR-342-5p played a role in Aβ formation by modulating BACE1 expression.