MicroRNA expression patterns in human anterior cingulate and motor cortex: A study of dementia with Lewy bodies cases and controls

Nelson, Peter T.; Wang, Wang‐Xia; Janse, Sarah; Thompson, Katherine

doi:10.1016/j.brainres.2017.11.009

Cited by 24 publications

(13 citation statements)

References 99 publications

(121 reference statements)

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“…This work demonstrates that LOAD affects the expression of lncRNAs in a sex-dependent manner. Other types of non-coding RNAs may play a sex-specific role in LOAD pathogenesis; however, this was not confirmed in a recent study on microRNAs (Nelson et al, 2018). These findings highlight that integrative multi-omics studies will be essential to understanding whether epigenomic changes directly affect gene expression patterns in LOAD.…”

Section: Apoementioning

confidence: 76%

Sex-dependent effect of APOE on Alzheimer's disease and other age-related neurodegenerative disorders

Gamache

Yun

Chiba‐Falek

2020

Disease Models &Amp; Mechanisms

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The importance of apolipoprotein E (APOE) in late-onset Alzheimer's disease (LOAD) has been firmly established, but the mechanisms through which it exerts its pathogenic effects remain elusive. In addition, the sex-dependent effects of APOE on LOAD risk and endophenotypes have yet to be explained. In this Review, we revisit the different aspects of APOE involvement in neurodegeneration and neurological diseases, with particular attention to sex differences in the contribution of APOE to LOAD susceptibility. We discuss the role of APOE in a broader range of age-related neurodegenerative diseases, and summarize the biological factors linking APOE to sex hormones, drawing on supportive findings from rodent models to identify major mechanistic themes underlying the exacerbation of LOAD-associated neurodegeneration and pathology in the female brain. Additionally, we list sex-by-genotype interactions identified across neurodegenerative diseases, proposing APOE variants as a shared etiology for sex differences in the manifestation of these diseases. Finally, we present recent advancements in ‘omics’ technologies, which provide a new platform for more in-depth investigations of how dysregulation of this gene affects the development and progression of neurodegenerative diseases. Collectively, the evidence summarized in this Review highlights the interplay between APOE and sex as a key factor in the etiology of LOAD and other age-related neurodegenerative diseases. We emphasize the importance of careful examination of sex as a contributing factor in studying the underpinning genetics of neurodegenerative diseases in general, but particularly for LOAD.

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Section: Apoementioning

confidence: 76%

Sex-dependent effect of APOE on Alzheimer's disease and other age-related neurodegenerative disorders

Gamache

Yun

Chiba‐Falek

2020

Disease Models &Amp; Mechanisms

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“…This present work significantly advances the field. Specific miRNAs play a critical role in brain aging, neuroinflammation, neurodegeneration, and brain trauma [112] miRNAs play major roles in cognitive impairment in both AD-like pathology and dementia with Lewy bodies [113,114]. For example, miR-455-3p may have protective effects against abnormal APP processing and Aβ-toxicity in AD [115].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties

et al. 2020

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Alzheimer's disease (AD) is the most common age-related form of dementia, associated with deposition of intracellular neuronal tangles consisting primarily of hyperphosphorylated microtubule-associated protein tau (p-tau) and extracellular plaques primarily comprising amyloid-β (Aβ) peptide. The p-tau tangle unit is a posttranslational modification of normal tau protein. Aβ is a neurotoxic peptide excised from the amyloid-β precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. MicroRNAs (miRNAs) are short, single-stranded RNAs that modulate protein expression as part of the RNA-induced silencing complex (RISC). We identified miR-298 as a repressor of APP, BACE1, and the two primary forms of Aβ (Aβ40 and Aβ42) in a primary human cell culture model. Further, we discovered a novel effect of miR-298 on posttranslational levels of two specific tau moieties. Notably, miR-298 significantly reduced levels of 55 and 50 kDa forms of the tau protein without significant alterations of total tau or other forms. In vivo overexpression of human miR-298 resulted in nonsignificant reduction of APP, BACE1, and tau in mice. Moreover, we identified two miR-298 SNPs associated with higher cerebrospinal fluid (CSF) p-tau and lower CSF Aβ42 levels in a cohort of human AD patients. Finally, levels of miR-298 varied in postmortem human temporal lobe between AD patients and age-matched non-AD controls. Our results suggest that miR-298 may be a suitable target for AD therapy.

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“…The brain also has an extremely complex architecture of functionally distinct cell types, with more than 40 distinct neuronal types in the cortex alone (Tasic et al 2016), so multitargeting by miRNAs with overlapping but distinct expression patterns across neuronal subtypes might be used to tune cell-type-specific expression. Perturbation of the expression of multiple miRNAs belonging to the brain cluster occurs in several diseases of the brain, including glioblastoma, Huntington's disease, and dementia with Lewy bodies (Skalsky and Cullen 2011;Soldati et al 2013;Nelson et al 2018). Changes in the levels of groups of miRNAs that cotarget together may yield large magnitude changes in the expression of multiply targeted mRNAs, potentially contributing to pathology.…”

Section: Discussionmentioning

confidence: 99%

Cotargeting among microRNAs in the brain

2019

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MicroRNAs (miRNAs) play roles in diverse developmental and disease processes. Distinct miRNAs have hundreds to thousands of conserved mRNA binding sites but typically direct only modest repression via single sites. Cotargeting of individual mRNAs by different miRNAs could potentially achieve stronger and more complex patterns of repression. By comparing target sets of different miRNAs, we identified hundreds of pairs of miRNAs that share more mRNA targets than expected (often by twofold or more) relative to stringent controls. Genetic perturbations revealed a functional overlap in neuronal differentiation for the cotargeting pair miR-138/miR-137. Clustering of all cotargeting pairs revealed a group of nine predominantly brain-enriched miRNAs that share many targets. In reporter assays, subsets of these miRNAs together repressed gene expression by five-to 10-fold, often showing cooperative repression. Together, our results uncover an unexpected pattern in which combinations of miRNAs collaborate to robustly repress cotargets, and suggest important developmental roles for cotargeting.

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MicroRNA expression patterns in human anterior cingulate and motor cortex: A study of dementia with Lewy bodies cases and controls

Abstract: A subset of miRNAs (some previously associated with α-synucleinopathy and/or directly targeting α-synuclein mRNA) were differentially expressed in AC and MO, which may help explain why these brain regions show differences in vulnerability to Lewy body pathology.

Cited by 24 publications

References 99 publications

Sex-dependent effect of APOE on Alzheimer's disease and other age-related neurodegenerative disorders

Sex-dependent effect of APOE on Alzheimer's disease and other age-related neurodegenerative disorders

MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties

Cotargeting among microRNAs in the brain

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