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

Abstract

Background: 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 candidate miRNAs previously showing compelling evidence in the literature in a large collection of brain samples from AD and control individuals. Methods: Brain tissue was derived from superior temporal gyrus (STG) and entorhinal cortex (EC) from 100 AD patients and 99 control individuals. Expression of six selected miRNAs was assessed either by qPCR (STG) or small RNA sequencing (EC). Brain region-dependent differential miRNA expression was assessed in a transgenic AD mouse model. All results were combined with those from other datasets by meta-analysis. Results: MiR-129-5p, miR-132-5p, and miR-138-5p were significantly downregulated in AD vs. controls both in STG and EC. In contrast, we found no strong evidence for differential miRNA expression for miR-125b-5p and miR-501-3p, which previously ranked high by meta-analysis. In addition, we observed miR-195-5p to be significantly upregulated in EC of AD, but not in STG. The brain region-specific nature of differential miR-195-5p expression was corroborated by targeted qPCR analyses in an AD transgenic mouse model. Conclusions: Using two different methods (qPCR and small RNA-seq) in two separate brain regions in ≈200 AD patients and controls we more than doubled the available sample size for most miRNAs tested. Differential miRNA expression analyses confirm the likely involvement of miR-129-5p, miR-132-5p, miR-138-5p, and miR-195-5p in AD pathogenesis.

Entorhinal cortex epigenome-wide association study highlights four novel loci showing differential methylation in Alzheimer’s disease

“…Snap-frozen, post-mortem human brain tissue from EC slices (Brodmann area BA28) from 91 AD patients and 92 elderly control individuals was obtained from the Oxford Brain Bank. The AD patients and healthy controls were part of the longitudinal, prospective Oxford Project to Investigate Memory and Aging (OPTIMA) using protocols which have been described in detail elsewhere (18). All subjects underwent a detailed clinical history, physical examination, assessment of cognitive function (Cambridge Examination of Mental Disorders of the Elderly (CAMDEX) (19) with the Cambridge Cognitive Examination (CAMCOG) and Mini-Mental State Examination (MMSE) biannually.…”

Sequestration of LINE-1 in novel cytosolic bodies 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 58 and both miRNAs are downregulated in brain pathologies from Alzheimer's Disease patients 59,60 . Activation of expression and mobility of transposable elements has been reported in a majority of neurological disorders 61 and certain cancers 62 .…”

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).…”