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Circulating micro-RNAs Differentially Expressed in Korean Alzheimer's Patients With Brain Aβ Accumulation Activate
Sakulrat Mankhong1,2, Sujin Kim1, Sohee Moon1
1Department of Pharmacology and Research Center for Controlling Intercellular Communication, College of Medicine, Inha University, Incheon, Republic of Korea.
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.
Insights
This study identified specific micro-RNAs (miRNAs) in Korean Alzheimer's disease (AD) patients that may contribute to amyloidogenesis, though their diagnostic utility as biomarkers is limited. These miRNAs influence amyloid precursor protein processing and target gene regulation in AD.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Extracellular vesicles (EVs) and micro-RNAs (miRNAs) are implicated in Alzheimer's disease (AD) pathogenesis.
- Blood-based miRNA biomarkers for AD show inconsistent diagnostic utility.
- This study focuses on Korean AD patients to identify novel blood miRNA biomarkers and investigate their role in amyloidogenesis.
Purpose of the Study:
- To discover differentially expressed miRNAs in Korean AD patients compared to cognitively normal (CN) and Parkinson's disease (PD) individuals.
- To evaluate the clinical performance of identified miRNAs as plasma and EV biomarkers for AD.
- To investigate the in vitro role of these miRNAs in amyloidogenesis and target gene regulation.
Main Methods:
- Differential expression analysis of miRNAs in AD, CN, and PD cohorts.
- Clinical performance evaluation of plasma and EV miRNAs in a larger cohort (N=251) and amyloid positron emission tomography (Aβ-PET) positive/negative subgroups.
- In vitro experiments to assess the impact of miRNAs on amyloid-beta (Aβ) production, β-secretase activity, and target gene expression.
Main Results:
- Three miRNAs (miR-122-5p, miR-210-3p, miR-590-5p) were significantly upregulated in AD patients.
- Diagnostic performance of plasma or EV miRNAs was limited (AUC < 0.8).
- Levels of these 3 miRNAs were higher in Aβ-PET positive participants; they induced Aβ production by activating CTF-β and downregulated key target genes (ADAM10, BDNF, JAG1).
Conclusions:
- The identified miRNAs show potential roles in Alzheimer's disease amyloidogenesis.
- Despite limited diagnostic value as standalone biomarkers, these miRNAs offer insights into AD pathogenesis.
- Further research is warranted to explore the functional significance of these miRNAs in AD onset and progression.
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