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Published on: January 28, 2014
Biomarkers
Jessica Diniz Pereira1,2, Lívia Cristina Ribeiro Teixeira1, Izabela Mamede Costa Andrade da Conceição3
1Faculty of Pharmacy - Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Background:
Alzheimer's disease (AD) is the most common type of dementia and accounts for around 70% of reported cases. MicroRNAs are small non-coding RNAs with highly conserved sequences, involved in gene modulation and several molecular mechanisms. miRNAs can be found in cerebrospinal fluid (CSF) and serve as potential biomarkers for AD diagnosis. This study aimed to perform an in silico analysis of miRNA expression in the CSF of AD patients compared to cognitively healthy controls and to conduct an analysis of the biological pathways regulated by these miRNAs.
Method:
Employing a machine learning approach, we identified the most differentially expressed miRNAs in AD, using datasets deposited in the Gene Expression Omnibus (GEO). These findings were further validated through a systematic literature review. Pathway enrichment analysis was conducted to identify the key biological pathways that exhibited greater significance after random pathway analysis.
Result:
Through the LightGBM machine learning algorithm, we selected miRNAs from GEO data with the best predictive values and matched them with the miRNAs found in the systematic review. The systematic review identified 24 studies that met the inclusion criteria. The miRNAs common to both approaches were 30a-3p, 193a-5p, 143-3p and 145-5p, with reduced expression in AD patients compared to controls. The key biological pathways involving the genes regulated by these miRNAs included the TGF-beta, ERBB signaling, MAPK pathways, and AP-1 pathway.
Conclusion:
Our results suggest that miRNAs 30a-3p, 193a-5p, 143-3p and 145-5p are involved in biological pathways related to AD and represent potential biomarkers. TGF-beta, ERBB and MAPK are pathways already related to AD in the literature. The novelty is the AP-1 pathway, which regulates cell death and apoptotic factors, its activation decondenses genomic regions and activates cell death pathways in neurons. Furthermore, the increase in Aβ1-42 elevates AP-1 mRNA levels in astrocytes, inducing apoptosis. These findings underscore the importance of the miRNAs in AD and offer potential advancements in the understanding of its pathophysiology, mainly involving the AP-1 pathway.
Keywords:
Alzheimer's disease, miRNAs, cerebrospinal fluid.
Acknowledgments:
CNPq e CAPES.
Insights
Four microRNAs (miRNAs) show reduced expression in Alzheimer's disease (AD) patients, potentially serving as novel biomarkers. These miRNAs regulate key pathways, including the newly identified AP-1 pathway, crucial for neuronal apoptosis.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Alzheimer's disease (AD) is the leading cause of dementia, affecting millions globally.
- MicroRNAs (miRNAs) are critical gene regulators found in cerebrospinal fluid (CSF), showing promise as AD biomarkers.
- Identifying specific miRNAs and their regulated pathways is vital for understanding AD pathophysiology.
Purpose of the Study:
- To identify differentially expressed miRNAs in the CSF of AD patients compared to controls using in silico analysis.
- To validate these miRNA findings through a systematic literature review.
- To analyze the biological pathways regulated by the identified miRNAs in AD.
Main Methods:
- Utilized machine learning (LightGBM) on Gene Expression Omnibus (GEO) datasets to find predictive miRNAs.
- Conducted a systematic literature review of 24 studies to identify relevant miRNAs.
- Performed pathway enrichment analysis to determine significant biological pathways.
Main Results:
- Identified four common miRNAs (30a-3p, 193a-5p, 143-3p, 145-5p) with decreased expression in AD patients.
- These miRNAs regulate established AD-related pathways (TGF-beta, ERBB, MAPK) and the novel AP-1 pathway.
- The AP-1 pathway's role in neuronal cell death and apoptosis was highlighted.
Conclusions:
- miRNAs 30a-3p, 193a-5p, 143-3p, and 145-5p are potential biomarkers for AD.
- The AP-1 pathway, involved in neuronal apoptosis, is a significant novel finding in AD pathophysiology.
- These miRNAs and pathways offer new avenues for understanding and potentially treating AD.
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