TY - JOUR
T1 - Circulating micro-RNAs Differentially Expressed in Korean Alzheimer’s Patients With Brain Aβ Accumulation Activate Amyloidogenesis
AU - Mankhong, Sakulrat
AU - Kim, Sujin
AU - Moon, Sohee
AU - Choi, Seong Hye
AU - Kwak, Hyo Bum
AU - Park, Dong Ho
AU - Shah, Pratik
AU - Lee, Phil Hyu
AU - Yang, Seong Wook
AU - Kang, Ju Hee
N1 - Publisher Copyright:
© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - Background: Roles for extracellular vesicles (EVs) enriched with micro-RNAs (miRNAs) have been proposed in Alzheimer’s disease (AD) pathogenesis, leading to the discovery of blood miRNAs as AD biomarkers. 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, and investigate their role in amyloidogenesis. Methods: We discovered miRNAs differentially expressed in AD (N = 8) from cognitively normal participants (CN, N = 7) or Parkinson’s disease (PD) patients (N = 8). We evaluated the clinical performance of these miRNAs in plasma of subgroup (N = 99) and in plasma EVs isolated from the total cohort (N = 251). The effects of miRNAs on amyloidogenesis and on the regulation of their target genes were investigated in vitro. Results: Among 17 upregulated and one downregulated miRNAs in AD (>twofold), miR-122-5p, miR-210-3p, and miR-590-5p were differentially expressed compared with CN or PD. However, the diagnostic performance of the selected plasma or EV miRNAs in total participants were limited (area under the curve < 0.8). Nevertheless, levels of 3 miRNAs in plasma or plasma EVs of participants who were amyloid positron emission tomography (Aβ-PET) positive were significantly higher than those from the Aβ-PET negative participants (p < .05). The selected miRNAs induced Aβ production (p < .05) through activation of β-cleavage of amyloid precursor protein (CTF-β; p < .01), and downregulated their target genes (ADAM metallopeptidase domain 10, Brain-derived neurotrophic factor, and Jagged canonical notch ligand 1; p < .05), which was further supported by pathway enrichment analysis of target genes of the miRNAs. Conclusion: In conclusion, despite of the limited diagnostic utility of selected miRNAs as plasma or plasma EV biomarkers, the discovered miRNAs may play a role in amyloidogenesis during AD onset and progression.
AB - Background: Roles for extracellular vesicles (EVs) enriched with micro-RNAs (miRNAs) have been proposed in Alzheimer’s disease (AD) pathogenesis, leading to the discovery of blood miRNAs as AD biomarkers. 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, and investigate their role in amyloidogenesis. Methods: We discovered miRNAs differentially expressed in AD (N = 8) from cognitively normal participants (CN, N = 7) or Parkinson’s disease (PD) patients (N = 8). We evaluated the clinical performance of these miRNAs in plasma of subgroup (N = 99) and in plasma EVs isolated from the total cohort (N = 251). The effects of miRNAs on amyloidogenesis and on the regulation of their target genes were investigated in vitro. Results: Among 17 upregulated and one downregulated miRNAs in AD (>twofold), miR-122-5p, miR-210-3p, and miR-590-5p were differentially expressed compared with CN or PD. However, the diagnostic performance of the selected plasma or EV miRNAs in total participants were limited (area under the curve < 0.8). Nevertheless, levels of 3 miRNAs in plasma or plasma EVs of participants who were amyloid positron emission tomography (Aβ-PET) positive were significantly higher than those from the Aβ-PET negative participants (p < .05). The selected miRNAs induced Aβ production (p < .05) through activation of β-cleavage of amyloid precursor protein (CTF-β; p < .01), and downregulated their target genes (ADAM metallopeptidase domain 10, Brain-derived neurotrophic factor, and Jagged canonical notch ligand 1; p < .05), which was further supported by pathway enrichment analysis of target genes of the miRNAs. Conclusion: In conclusion, despite of the limited diagnostic utility of selected miRNAs as plasma or plasma EV biomarkers, the discovered miRNAs may play a role in amyloidogenesis during AD onset and progression.
KW - Alzheimer’s disease
KW - Beta-amyloid
KW - Blood biomarkers
KW - Extracellular vesicle
KW - Micro-RNA
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U2 - 10.1093/gerona/glac106
DO - 10.1093/gerona/glac106
M3 - Article
C2 - 35532940
AN - SCOPUS:85146601811
SN - 1079-5006
VL - 78
SP - 292
EP - 303
JO - Journals of Gerontology - Series A Biological Sciences and Medical Sciences
JF - Journals of Gerontology - Series A Biological Sciences and Medical Sciences
IS - 2
ER -