{'fraction_non_alphanumeric': 0.0332512315270936, 'fraction_numerical': 0.020935960591133004, 'mean_word_length': 5.169620253164557, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Circulating micro-RNAs Differentially Expressed in Korean Alzheimer’s Patients with Brain Aβ Accumulation Activate Amyloidogenesis


 BACKGROUNDA role for extracellular vesicles (EVs) enriched with micro-RNAs (miRNAs) has been proposed in Alzheimer’s disease (AD) pathogenesis, leading to the discovery of blood miRNAs as biomarkers of AD. However, the diagnostic utility of specific miRNAs is not consistent. This study aimed to discover blood miRNAs that are differentially expressed in Korean AD patients, evaluate their clinical performance in plasma or plasma EVs, and investigate their role in amyloidogenesis. METHODSBlood from 15 (7 cognitively normal [CN] and 8 AD) out of 262 subjects (59 CN, 105 mild cognitive impairment [MCI], 98 AD) and 8 Parkinson’s disease (PD) patients was used to discover miRNAs differentially expressed in AD. We evaluated the clinical performance of these miRNAs in plasma of a subgroup of 100 subjects (51 CN, 22 MCI, 27 AD) and in plasma EVs isolated from the total cohort in a cross-sectional design. The effects of miRNAs on amyloid b (Ab) production and expression of their target genes were investigated in neuronal culture systems. RESULTSAmong 17 upregulated, and one downregulated miRNAs in AD (>2-fold), three upregulated miRNAs (miR-122-5p, miR-210-3p, and miR-590-5p) that were differentially expressed in AD compared with CN or PD were selected. Diagnostic utility for discrimination of AD or MCI from CN of the selected miRNAs in plasma or plasma EV was not high. Nevertheless, the levels of three miRNAs in plasma or plasma EVs of subjects who were Ab positive on positron emission tomography (PET) were significantly higher than those from subjects who were Ab-PET negative. Furthermore, the selected miRNAs induced Ab production through activation of b-cleavage of amyloid precursor protein and downregulated their target genes. Pathway enrichment and protein interaction network analysis of target genes of the miRNAs further supported the roles of the selected miRNAs in amyloidogenesis. CONCLUSIONThe diagnostic utility of circulating miR-122-5p, miR-210-3p, and miR-590-5p to discriminate AD from CN was modest. However, these miRNAs were highly expressed in patients with amyloid accumulation, which was supported by in vitro analysis of amyloidogenesis. Our results suggest that blood-based miRNA biomarkers may play a role in amyloidogenesis during AD onset and progression.