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Genome-wide profiling and predicted significance of post-mortem brain microRNA in Alzheimer's disease
Adriane D Henriques1, Wilcelly Machado-Silva1, Renata E P Leite2
1Federal University of Brasilia (UnB), Brasília, DF, Brazil.
Background:
MicroRNAs (miRNAs) emerged as regulatory elements, with up to 70 % of all miRNAs found in the brain, playing key roles in the onset of Alzheimer's disease (AD).
Objective:
to broadly assess the expression levels of miRNAs in post-mortem brain (PMB) samples of individuals deceased with or without AD.
Methods:
A high-throughput microarray platform was used to sketch miRNA samples isolated from superior and middle temporal gyrus of A+T+ AD cases, compared to samples from age- and sex-matched AD-devoid donors, all pulled from the University of São Paulo's Brain Biobank. The miRNAs identified by microarray were subjected to validation with specific qRT-PCR assays employing independent PMB samples.
Results:
The analyses yielded 6 miRNAs differentially expressed (miR-30e_3p; miR-365b_5p; miR-664_3p; miR-1202; miR-4286; miR-4449), and their interplay with specific AD-related genes and signaling pathways was explored using bioinformatics analyses (including the KEGG package, mirPath v.3). In the end, 3 miRNAs, 7 target genes and 11 pathways were found closely interrelated and implicated with the AD pathophysiology.
Conclusion:
A dysregulation on a subset of these miRNAs appear to affect a range of genes (notably PTEN) and pathways (emphasis to PI3K-AKT) so to provide grounds for neuronal death by apoptotic signaling, autophagy and/or oxidative damage.
Insights
Six microRNAs (miRNAs) are differentially expressed in Alzheimer's disease (AD) brains, impacting genes and pathways linked to neuronal death. This finding offers new insights into AD pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- MicroRNAs (miRNAs) are key regulatory elements, with a significant proportion found in the brain.
- miRNAs play critical roles in the development and progression of Alzheimer's disease (AD).
Purpose of the Study:
- To comprehensively evaluate miRNA expression levels in post-mortem brain (PMB) samples from individuals with and without AD.
- To identify specific miRNAs implicated in the pathophysiology of Alzheimer's disease.
Main Methods:
- Utilized high-throughput microarray analysis on temporal gyrus PMB samples from AD and control cases.
- Validated differentially expressed miRNAs using quantitative real-time PCR (qRT-PCR) on independent PMB samples.
- Employed bioinformatics analyses (KEGG, mirPath v.3) to explore miRNA-gene-pathway interactions.
Main Results:
- Identified 6 differentially expressed miRNAs: miR-30e_3p, miR-365b_5p, miR-664_3p, miR-1202, miR-4286, and miR-4449.
- Discovered close interrelationships between 3 miRNAs, 7 target genes (including PTEN), and 11 signaling pathways (including PI3K-AKT).
Conclusions:
- Dysregulation of specific miRNAs affects genes and pathways crucial to neuronal death mechanisms.
- These findings suggest that miRNA dysregulation contributes to AD pathogenesis via apoptosis, autophagy, and oxidative damage pathways.
