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

Abstract

Dysregulation of microRNAs (miRNAs) is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). Hitherto, sample sizes from differential miRNA expression studies in AD are exceedingly small aggravating any biological inference. To overcome this limitation, we investigated six candidate miRNAs in a large collection of brain samples. Brain tissue was derived from superior temporal gyrus (STG) and entorhinal cortex (EC) from 99 AD patients and 91 controls. MiRNA expression was examined by qPCR (STG) or small RNA sequencing (EC). Brain region-dependent differential miRNA expression was investigated in a transgenic AD mouse model using qPCR and FISH. Total RNA sequencing was used to assess differential expression of miRNA target genes. MiR-129-5p, miR-132-5p, and miR-138-5p were significantly downregulated in AD vs. controls both in STG and EC, while miR-125b-5p and miR-501-3p showed no evidence for differential expression in this dataset. In addition, miR-195-5p was significantly upregulated in EC but not STG in AD patients. The brain region-specific pattern of miR-195-5p expression was corroborated in vivo in transgenic AD mice. Total RNA sequencing identified several novel and functionally interesting target genes of these miRNAs involved in synaptic transmission (GABRB1), the immune-system response (HCFC2) or AD-associated differential methylation (SLC16A3). Using two different methods (qPCR and small RNA-seq) in two separate brain regions in 190 individuals we more than doubled the available sample size for most miRNAs tested. Differential gene expression analyses confirm the likely involvement of miR-129-5p, miR-132-5p, miR-138-5p, and miR-195-5p in AD pathogenesis and highlight several novel potentially relevant target mRNAs.

Detection of a Parkinson's Disease–Specific MicroRNA Signature in Nasal and Oral Swabs

“…19 These seemingly conflicting results could possibly be attributed to differences in miR expression that are specific to disease stages and tissue types, as has been documented in neurodegenerative disorders. 35 Our work thus reinforces the usefulness of certain miRNAs from our previous miRNA-seq experiments and illustrates their applicability in a more easily accessible specimen, available from routine clinical diagnostics. In accord with miRNAs being suitable LBD biomarkers, a recent study reported a consistent deregulation of 12 miRNAs across the RBD continuum, including DaT-negative iRBD, DaT-positive iRBD, and LBD phenoconverted iRBD, both in cross-sectional and longitudinal analyses.…”

“…This result differs from previous findings indicating that miR‐486p is upregulated in gut biopsies of PD cases 19 . These seemingly conflicting results could possibly be attributed to differences in miR expression that are specific to disease stages and tissue types, as has been documented in neurodegenerative disorders 35 . Our work thus reinforces the usefulness of certain miRNAs from our previous miRNA‐seq experiments and illustrates their applicability in a more easily accessible specimen, available from routine clinical diagnostics.…”

Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer’s disease

“…Postmortem brain tissues from four patients with AD and five age-matched controls diagnosed by neurology were provided by the Tissue Bank of the Institute of Geriatrics, Chinese PLA General Hospital, and Chinese PLA Medical Academy, and a detailed description of the patient information is provided in previous studies ( 58 , 84 ). Total RNA-seq data from entorhinal cortex samples from 90 patients with AD and 84 healthy donors were provided by the Oxford Brain Bank ( 85 ), and the use of these human tissue samples for this study was approved by the Ethics Committees of the University of Lübeck. This study was approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology.…”

Sequestration of LINE‐1 in cytosolic aggregates by MOV10 restricts retrotransposition

“…MREs in Mov10 for all four tested miRNAs miR‐138‐5p, miR‐30‐5p, miR‐16‐5p, and miR‐153‐3p in mESCs are conserved in the 3'UTR sequence of hMOV10, raising the possibility that this mechanism regulating MOV10 expression may also be conserved in humans. Of note, miR‐138‐5p and miR‐153‐3p are highly expressed in the human brain (Ludwig et al , 2016), and both miRNAs are downregulated in brain pathologies from Alzheimer's disease patients (Long et al , 2012; preprint: Dobricic et al , 2021). The activation of expression and mobility of transposable elements has been reported in a majority of neurological disorders (Terry & Devine, 2020) and certain cancers (Xiao‐Jie et al , 2016).…”