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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.

SUBMITTER: Li QS

PROVIDER: S-EPMC8021900 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Neuroinflammation is proposed as one of the mechanisms by which Alzheimer's disease pathology, including amyloid-β plaques, leads to neuronal death and dysfunction. Increases in the expression of markers of microglia, the main neuroinmmune cell, are widely reported in brains from patients with Alzheimer's disease, but the literature has not yet been systematically reviewed to determine whether this is a consistent pathological feature. A systematic search was conducted in Medline, Embase and PsychINFO for articles published up to 23 February 2017. Papers were included if they quantitatively compared microglia markers in post-mortem brain samples from patients with Alzheimer's disease and aged controls without neurological disease. A total of 113 relevant articles were identified. Consistent increases in markers related to activation, such as major histocompatibility complex II (36/43 studies) and cluster of differentiation 68 (17/21 studies), were identified relative to nonneurological aged controls, whereas other common markers that stain both resting and activated microglia, such as ionized calcium-binding adaptor molecule 1 (10/20 studies) and cluster of differentiation 11b (2/5 studies), were not consistently elevated. Studies of ionized calcium-binding adaptor molecule 1 that used cell counts almost uniformly identified no difference relative to control, indicating that increases in activation occurred without an expansion of the total number of microglia. White matter and cerebellum appeared to be more resistant to these increases than other brain regions. Nine studies were identified that included high pathology controls, patients who remained free of dementia despite Alzheimer's disease pathology. The majority (5/9) of these studies reported higher levels of microglial markers in Alzheimer's disease relative to controls, suggesting that these increases are not solely a consequence of Alzheimer's disease pathology. These results show that increased markers of microglia are a consistent feature of Alzheimer's disease, though this seems to be driven primarily by increases in activation-associated markers, as opposed to markers of all microglia.

Project description:Background The trigeminal ganglion contains neurons that relay sensations of pain, touch, pressure, and many other somatosensory modalities to the central nervous system. The ganglion is also a reservoir for latent herpes virus 1 infection. To gain a better understanding of molecular factors contributing to migraine and headache, transcriptome analyses were performed on postmortem human trigeminal ganglia. Methods RNA-Seq measurements of gene expression were conducted on small sub-regions of 16 human trigeminal ganglia. The samples were also characterized for transcripts derived from viral and microbial genomes. Herpes simplex virus 1 (HSV-1) antibodies in blood were measured using the luciferase immunoprecipitation assay. Results Observed molecular heterogeneity could be explained by sampling of anatomically distinct sub-regions of the excised ganglia consistent with neurally-enriched and non-neural, i.e. Schwann cell, enriched subregions. The levels of HSV-1 transcripts detected in trigeminal ganglia correlated with blood levels of HSV-1 antibodies. Multiple migraine susceptibility genes were strongly expressed in neurally-enriched trigeminal samples, while others were expressed in blood vessels. Conclusions These data provide a comprehensive human trigeminal transcriptome and a framework for evaluation of inhomogeneous post-mortem tissues through extensive quality control and refined downstream analyses for RNA-Seq methodologies. Expression profiling of migraine susceptibility genes identified by genetic association appears to emphasize the blood vessel component of the trigeminovascular system. Other genes displayed enriched expression in the trigeminal compared to dorsal root ganglion, and in-depth transcriptomic analysis of the KCNK18 gene underlying familial migraine shows selective neural expression within two specific populations of ganglionic neurons. These data suggest that expression profiling of migraine-associated genes can extend and amplify the underlying neurobiological insights obtained from genetic association studies.

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

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