Integrated miRNA-Seq and mRNA-Seq Study to Identify miRNAs Associated With Alzheimer’s Disease Using Post-mortem Brain Tissue Samples

Abstract

Alzheimer’s disease (AD), the leading form of dementia, is associated with abnormal tau and β-amyloid accumulation in the brain. We conducted a miRNA-seq study to identify miRNAs associated with AD in the post-mortem brain from the inferior frontal gyrus (IFG, n = 69) and superior temporal gyrus (STG, n = 81). Four and 64 miRNAs were differentially expressed (adjusted p-value < 0.05) in AD compared to cognitively normal controls in the IFG and STG, respectively. We observed down-regulation of several miRNAs that have previously been implicated in AD, including hsa-miR-212-5p and hsa-miR-132-5p, in AD samples across both brain regions, and up-regulation of hsa-miR-146a-5p, hsa-miR-501-3p, hsa-miR-34a-5p, and hsa-miR-454-3p in the STG. The differentially expressed miRNAs were previously implicated in the formation of amyloid-β plaques, the dysregulation of tau, and inflammation. We have also observed differential expressions for dozens of other miRNAs in the STG, including hsa-miR-4446-3p, that have not been described previously. Putative targets of these miRNAs (adjusted p-value < 0.1) were found to be involved in Wnt signaling pathway, MAPK family signaling cascades, sphingosine 1-phosphate (S1P) pathway, adaptive immune system, innate immune system, and neurogenesis. Our results support the finding of dysregulated miRNAs previously implicated in AD and propose additional miRNAs that appear to be dysregulated in AD for experimental follow-up.

Differential microRNA expression analyses across two brain regions in Alzheimer’s disease

“…miR-125b-5p and miR-501-3p, were not replicated in our independent brain dataset and, as a result, now only show reduced overall evidence of differential expression upon meta-analysis. We note that of these two miRNAs only miR-501-3p was studied in the newly included paper by Li & Cai, 2021, who found a significant up-regulation in AD vs. controls (and in line with the previous meta-analysis). Notwithstanding, the overall meta-analytic evidence combining all newly available data for this miRNA showed reduced statistical support (P-value 1.56E-06) when compared to our previous study (P-value 2.03E-11).…”

“…To assess the overall evidence of differential expression of the six miRNAs tested here we updated our earlier meta-analyses by combining 1) results from the database of Takousis et al ., 2) STG-based results from the current study, and 3) data from additional studies testing any of the six miRNAs for differential miRNA expression in human brain samples not included in our previous report (Li & Cai, 2021; Patrick et al, 2017).…”

Systematic Search for Novel Circulating Biomarkers Associated with Extracellular Vesicles in Alzheimer’s Disease: Combining Literature Screening and Database Mining Approaches

“…The function of hsa-miR-146a in AD has been extensively studied. Recently, hsa-miR-146a upregulation was observed in postmortem AD brain tissue [87]. The effect of hsa-miR-146a as a switch for reduced proinflammatory microglial phenotypes was proposed [88].…”

Small Molecule Drugs Targeting Non-Coding RNAs as Treatments for Alzheimer’s Disease and Related Dementias

“…We and other labs have shown that miR-132 is a key miRNA downregulated in the early stages of ADRD before significant neuronal death occurs [ 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ]. miR-132 overexpression via viral vectors or oligonucleotide mimics exerts neuroprotective effects, delays neurodegeneration, and rescues behavioral deficits in several animal models of ADRD [ 92 , 96 ].…”