miR‐186 is decreased in aged brain and suppresses <scp>BACE</scp>1 expression

Kim, Jae Kwang; Yoon, Hyuk; Chung, Dah Eun Chloe; Brown, Jennifer; Belmonte, Krystal Courtney D.; Kim, Jung-Su

doi:10.1111/jnc.13507

Cited by 79 publications

(51 citation statements)

References 87 publications

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“…The reduced expression of these microRNAs may result in the elevated expression and function of BACE1, thus causing aberrant Aβ production as the characteristics of the brains from humans and mice with AD. In addition, overexpressed miR-186 in neuronal cells can result in reduced Aβ level by suppressing BACE1 expression; however, the down-regulated endogenous miR-186 can cause the increased BACE1 level (23). These findings provide the molecular mechanisms associated with BACE1, APP and Aβ deregulation in AD and new perspectives for the etiology of this disease.…”

Section: Micrornas Involvement In Ad Aβ Regulation Mediated By Micrormentioning

confidence: 87%

The Regulation of microRNAs in Alzheimer's Disease

Kou

Chen

2020

Front. Neurol.

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MicroRNAs are small non-coding nucleic acids that are responsible for regulating the gene expression by binding to the coding region and 3' and 5' un-translated region of target messenger RNA. Approximately 70% of known microRNAs are expressed in the brain and increasing evidences demonstrate the possible involvement of microRNAs in Alzheimer's disease (AD) according to the statistics. The characteristic symptoms of AD are the progressive loss of memory and cognitive functions due to the deposition of amyloid β (Aβ) peptide, intracellular aggregation of hyperphosphorylated Tau protein, the loss of synapses, and neuroinflammation, as well as dysfunctional autophagy. Therefore, microRNA-mediated regulation for above-mentioned changes may be the potential therapeutic strategies for AD. In this review, the role of specific microRNAs involved in AD and corresponding applications are systematically discussed, including positive effects associated with the reduction of Aβ or Tau protein, the protection of synapses, the inhibition of neuroinflammation, the mitigation of aging, and the induction of autophagy in AD. It will be beneficial to develop effective targets for establishing a cross link between pharmacological intervention and AD in the near future.

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Section: Micrornas Involvement In Ad Aβ Regulation Mediated By Micrormentioning

confidence: 87%

The Regulation of microRNAs in Alzheimer's Disease

Kou

Chen

2020

Front. Neurol.

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“…miR-186-5p is a highly conserved miRNA in mammals, expressed in the spinal cord and across multiple brain subregions, with enriched expression in neurons (74). Furthermore, expression of this miRNA can be regulated as a physiological response to stress in intestinal, prefrontal cortex, and hippocampal tissues (75,76), and by extrinsic factors, such as methamphetamine or alcohol intake (77,78).…”

Section: )mentioning

confidence: 99%

MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons

Silva

Rodrigues

Fernandes

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Homeostatic synaptic scaling is a negative feedback response to fluctuations in synaptic strength induced by developmental or learning-related processes, which maintains neuronal activity stable. Although several components of the synaptic scaling apparatus have been characterized, the intrinsic regulatory mechanisms promoting scaling remain largely unknown. MicroRNAs may contribute to posttranscriptional control of mRNAs implicated in different stages of synaptic scaling, but their role in these mechanisms is still undervalued. Here, we report that chronic blockade of glutamate receptors of the AMPA and NMDA types in hippocampal neurons in culture induces changes in the neuronal mRNA and miRNA transcriptomes, leading to synaptic upscaling. Specifically, we show that synaptic activity blockade persistently down-regulates miR-186-5p. Moreover, we describe a conserved miR-186-5p-binding site within the 3′UTR of the mRNA encoding the AMPA receptor GluA2 subunit, and demonstrate that GluA2 is a direct target of miR-186-5p. Overexpression of miR-186 decreased GluA2 surface levels, increased synaptic expression of GluA2-lacking AMPA receptors, and blocked synaptic scaling, whereas inhibition of miR-186-5p increased GluA2 surface levels and the amplitude and frequency of AMPA receptor-mediated currents, and mimicked excitatory synaptic scaling induced by synaptic inactivity. Our findings elucidate an activity-dependent miRNA-mediated mechanism for regulation of AMPA receptor expression.

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“…β-Site amyloid precursor protein (APP) cleaving enzyme 1 (β-secretase, BACE1) is a critical enzyme catalyzing amyloid β (Aβ) peptide generation by cleaving APP, and BACE1 activation is a hallmark of early stage cognitive deficits and plays an important role in progressive conversion to AD. Previously, several miRNAs have been demonstrated to be involved in post-transcriptional regulation of BACE1, including miR-9, miR-29, miR-107, miR-186, miR-188, miR-298, and miR-328 [ 40 , 41 ]. Alterations in specific miRNA levels can upregulate expression and stability of BACE1 protein, which in turn contributes to synaptic and cognitive deficits.…”

Section: Introductionmentioning

confidence: 99%

NF-κB-regulated microRNA-574-5p underlies synaptic and cognitive impairment in response to atmospheric PM2.5 aspiration

Gao

et al. 2017

Part Fibre Toxicol

111

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BackgroundPM2.5 (particulate matter ≤ 2.5 μm) is one of the leading environmental risk factors for the global burden of disease. Whereas increasing evidence has linked the adverse roles of PM2.5 with cardiovascular and respiratory diseases, limited but growing emerging evidence suggests that PM2.5 exposure can affect the nervous system, causing neuroinflammation, synaptic dysfunction and cognitive deterioration. However, the molecular mechanisms underlying the synaptic and cognitive deficits elicited by PM2.5 exposure are largely unknown.MethodsC57BL/6 mice received oropharyngeal aspiration of PM2.5 (1 and 5 mg/kg bw) every other day for 4 weeks. The mice were also stereotaxically injected with β-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE1) shRNA or LV-miR-574-5p lentiviral constructs in the absence or presence of PM2.5 aspiration at 5 mg/kg bw every other day for 4 weeks. Spatial learning and memory were assessed with the Morris water maze test, and synaptic function integrity was evaluated with electrophysiological recordings of long-term potentiation (LTP) and immunoblot analyses of glutamate receptor subunit expression. The expression of α-secretase (ADAM10), BACE1, and γ-secretase (nicastrin) and the synthesis and accumulation of amyloid β (Aβ) were measured by immunoblot and enzyme-linked immunosorbent assay (ELISA). MicroRNA (miRNA) expression was screened with a microRNA microarray analysis and confirmed by real-time quantitative reverse transcription PCR (qRT-PCR) analysis. Dual-luciferase reporter gene and chromatin immunoprecipitation (ChIP) analyses were used to detect the binding of miR-574-5p in the 3’UTR of BACE1 and NF-κB p65 in the promoter of miR-574-5p, respectively.ResultsPM2.5 aspiration caused neuroinflammation and deteriorated synaptic function integrity and spatial learning and memory, and the effects were associated with the induction of BACE1. The action was mediated by NF-κB p65-regulated downregulation of miR-574-5p, which targets BACE1. Overexpression of miR-574-5p in the hippocampal region decreased BACE1 expression, restored synaptic function, and improved spatial memory and learning following PM2.5 exposure.ConclusionsTaken together, our findings reveal a novel molecular mechanism underlying impaired synaptic and cognitive function following exposure to PM2.5, suggesting that miR-574-5p is a potential intervention target for the prevention and treatment of PM2.5-induced neurological disorders.Electronic supplementary materialThe online version of this article (10.1186/s12989-017-0215-3) contains supplementary material, which is available to authorized users.

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miR‐186 is decreased in aged brain and suppresses BACE1 expression

Cited by 79 publications

References 87 publications

The Regulation of microRNAs in Alzheimer's Disease

The Regulation of microRNAs in Alzheimer's Disease

MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons

NF-κB-regulated microRNA-574-5p underlies synaptic and cognitive impairment in response to atmospheric PM2.5 aspiration

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