Micro RNA’s (mirna’s) may help explain expression of multiple genes in Alzheimer’s Frontal Cortex

Abstract

MicroRNA's (miRNA's) are non-coding RNA's that can regulate gene expression. miRNA's are small (~22 nt) and can bind by complementation to mRNA's resulting in direct degradation and/or interference with translation. We used paired-end RNAseq and small RNAseq to examine expression of mRNA's and miRNA's, respectively, in total RNA's isolated from frontal cortex of Alzheimer's disease (AD) and control (CTL) subjects. mRNA's were aligned to the hg38 human genome using Tophat2/Bowtie2 and relative expression levels determined by Cufflinks as FPKM (fragments per kilobase of exon per million mapped reads). miRNA's were aligned to the hg19 human genome and quantitated as number of mature known miRNA reads with miRDeep*. Using a false-discovery rate (FDR) of 10% (FDR ≤ 0.10) applied to 11,794 genes with FPKM > 2.0, we identified 55 genes upregulated in AD and 191 genes downregulated in AD. The top 145 miRNA's with the highest mean expression were mostly under-expressed in AD (132/145 miRNAs had AD/CTL < 1.0)). AD samples had increased coefficients of variation for miRNA and mRNA expression, implying greater heterogeneity. miRTAR analysis showed that 32 (58%) of the mRNA genes upregulated in AD could be controlled by one or more of 60 miRNA's under-expressed >1.5-fold in AD (AD/CTL < 0.67). AD frontal cortex gene expression analysis showed extensive regulation by miRNAs that appear to interact with the majority of overexpressed protein coding genes. The temporal sequence of appearance in AD brain and etiologies of this extensive, heterogeneous regulation by miRNA's are unknown. (243 words)

Alzheimer’s Disease Frontal Cortex Mitochondria Show a Loss of Individual Respiratory Proteins but Preservation of Respiratory Supercomplexes

“…Blocks of slow frozen cortical ribbon from human frontal cortex were obtained from the University of Virginia Brain Resource Facility. These samples were used in our earlier work [ 11 ]. Demographics of the brain samples used for RNA sequencing (RNAseq) and mitochondrial preparation and immunoblotting are given in Supplemental File 1 .…”

Serum Glycoproteomics and Identification of Potential Mechanisms Underlying Alzheimer’s Disease

“…FAF2 has an important role in endoplasmic reticulum-associated degradation, which mediates ubiquitin-dependent degradation of misfolded ER proteins [ 46 ]. Significant underexpression of FAF2 was determined in the frontal cortex of AD patients [ 47 ]. SIRT4 was downregulated in AD patients.…”

RNA Sequencing Reveals Small and Variable Contributions of Infectious Agents to Transcriptomes of Postmortem Nervous Tissues From Amyotrophic Lateral Sclerosis, Alzheimer’s Disease and Parkinson’s Disease Subjects, and Increased Expression of Genes From Disease-Activated Microglia

“…Our methods for tissue acquisition, RNA seq analyses and bioinformatics have been described in multiple publications (Bennett et al, 2016; Brohawn et al, 2016, 2018; Bennett and Keeney, 2017; Ladd et al, 2017). The particular tissue sets for ALS (Bennett et al, 2016; Brohawn et al, 2016; Ladd et al, 2017), AD (Bennett and Keeney, 2017) 2 and PD (see text footnote 1) have been previously described. Briefly, tissues from persons with sporadic NDD’s were stored at -80 degrees and blocks dissected from these unfixed, frozen specimens.…”

“…We acquired postmortem samples of CNS tissues from sporadic NDD cases and carried out moderate-high density PE RNA sequencing on total RNA to seek systems biology understandings of disease pathogenesis in ALS, AD, and PD (Bennett et al, 2016; Brohawn et al, 2016; Bennett and Keeney, 2017; Ladd et al, 2017) (see also 1 ).…”