CoChat
Sign Up
Cited by 102Alzheimer's disease research and treatmentsMicroRNA in disease regulationNeuroinflammation and Neurodegeneration Mechanisms

miR‐186 is decreased in aged brain and suppresses BACE 1 expression

Open access
Kim, Jaekwang, Yoon, Hyejin, Chung, Dah‐eun, Brown, Jennifer L., Belmonte, Krystal C, Kim, Jungsu·2016·Journal of Neurochemistry
DOI 10.1111/jnc.13507PMC PMC4837067
Open this paper in CoChat — free account

Abstract

Accumulation of amyloid β (Aβ) in the brain is a key pathological hallmark of Alzheimer's disease (AD). Because aging is the most prominent risk factor for AD, understanding the molecular changes during aging is likely to provide critical insights into AD pathogenesis. However, studies on the role of mi RNA s in aging and AD pathogenesis have only recently been initiated. Identifying mi RNA s dysregulated by the aging process in the brain may lead to novel understanding of molecular mechanisms of AD pathogenesis. Here, we identified that miR‐186 levels are gradually decreased in cortices of mouse brains during aging. In addition, we demonstrated that miR‐186 suppresses β‐site amyloid precursor protein‐cleaving enzyme 1 (BACE 1) expression by directly targeting the 3′UTR of Bace1 mRNA in neuronal cells. In contrast, inhibition of endogenous miR‐186 significantly increased BACE 1 levels in neuronal cells. Importantly, miR‐186 over‐expression significantly decreased Aβ level by suppressing BACE 1 expression in cells expressing human pathogenic mutant amyloid precursor protein. Taken together, our data demonstrate that miR‐186 is a potent negative regulator of BACE 1 in neuronal cells and it may be one of the molecular links between brain aging and the increased risk for AD during aging. image We identified that miR‐186 levels are gradually decreased in mouse cortices during aging. Furthermore, we demonstrated that miR‐186 is a novel negative regulator of beta‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1) expression in neuronal cells. Therefore, we proposed that reduction in miR‐186 levels during aging may lead to the up‐regulation of BACE1 in the brain, thereby increasing a risk for Alzheimer's disease in aged individuals. Read the Editorial Highlight for this article on page 308.

AI snapshot

Written from the paper’s full text.

TL;DR

miR-186 decreases in mouse cortex during aging and directly suppresses BACE1 expression in neuronal cells. Overexpressing miR-186 lowers BACE1 and secreted Aβ, suggesting a possible molecular link between brain aging and Alzheimer’s disease risk.

Key findings

  • miR-186 expression was significantly decreased in mouse cortices at 13 months versus 2 months of age, with a trend toward further decrease at 24 months.
  • miR-186 directly targets two predicted sites in the 3′UTR of mouse *Bace1* mRNA; overexpression reduced luciferase activity, decreased BACE1 mRNA, and lowered BACE1 protein dose-dependently in Neuro-2a cells, while seed-site mutation abolished the luciferase effect.
  • Inhibiting endogenous miR-186 with LNA-based anti-miR-186 significantly increased BACE1 protein levels but did not affect BACE1 mRNA, suggesting basal translational suppression.
  • In 7PA2 cells expressing human APP770 with the Indiana mutation, miR-186 overexpression markedly decreased cellular CTFβ, secreted sAPPβ, and total Aβ, including Aβ40 and Aβ42; miR-186 levels were not affected by H2O2-induced oxidative stress or LPS-induced inflammation.

Methods

  • Wild-type C57BL/6J mice were sacrificed at different ages; cortical primary astrocytes and neurons were prepared, and Neuro-2a and 7PA2 cells were used for mechanistic experiments.
  • qRT-PCR measured miRNA/mRNA levels; luciferase reporter assays used full or partial mouse *Bace1* 3′UTR constructs with wild-type or mutated seed-match sites; Western blot measured APP, BACE1, CTFα, CTFβ, sAPPα, sAPPβ, and Aβ.
  • Statistical testing used Levene Median and Kolmogorov-Smirnov tests, then two-tailed Student’s t-test or one-way ANOVA with post-hoc analysis; data are mean ± SEM.

Limitations

  • The paper states that it cannot address the cause of miR-186 reduction in aged brain and that further in vivo animal studies are warranted to determine whether miR-186 regulates cognition and memory during aging and whether it has therapeutic effects for AD.
  • The paper notes that understanding of miRNA roles in human brain aging remains limited, and it cites conflicting reports of miR-186 levels in AD brain regions.
  • Evident from the text: most mechanistic evidence comes from neuronal cell lines and primary cells rather than in vivo models, and the Aβ-lowering result uses the 7PA2 mutant APP cell model.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/jnc.13507

Cites

86 of 86 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

31 of 70 cited sources checked · 19 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Expression and activity of BACE1 are increased during aging in the brains of mice, rats and humans.

    “Previous studies consistently reported that expression and activity of BACE1 are increased during aging in the brains mice, rats and humans (Boissonneault et al. 2009, Che et al. 2014, Fukumoto et al. 2004, Rossner et al. 2006), raising the possibility of a link between aging-associated alterations in BACE1 and the increased risk for AD.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Boissonneault et al. 2009

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Che et al. 2014 source
    • cites Fukumoto et al. 2004 source

      The “BACE Activity Increases in the Brain with Aging” section and Figure 2 report increased BACE activity with age in mice and humans. But the paper studied mice, monkeys, and humans—not rats—and its “There Are No Significant Changes in Brain BACE Protein Levels with Aging” section and Figure 3 report no significant age-related increase in BACE protein levels. No page numbers are provided in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
  • Premisecitation

    Inhibition of BACE1 by RNAi-mediated knock-down or genetic deletion ameliorates Aβ-associated pathologies and cognitive deficits in mouse models of Aβ-amyloidosis.

    “In fact, several studies unequivocally demonstrated that inhibition of BACE1 by RNAi-mediated knock-down or genetic deletion ameliorates Aβ-associated pathologies and cognitive deficits in mouse models of Aβ-amyloidosis (Laird et al. 2005, Luo et al. 2001, McConlogue et al. 2007, Ohno et al. 2004, Singer et al. 2005).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Laird et al. 2005 source
    • cites Luo et al. 2001 source
    • cites McConlogue et al. 2007 source
  • Premisecitation

    Up-regulation of BACE1 protein levels during aging is not due to the change of its mRNA levels.

    “However, up-regulation of BACE1 protein levels during aging is not due to the change of its mRNA levels (Hebert et al. 2008, Boissonneault et al. 2009).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Hebert et al. 2008 source

      The Results report increased BACE1 protein in a subgroup of sporadic Alzheimer’s disease patients while BACE1 mRNA remained essentially unchanged. The separate Results passage on brain development also reports stable BACE1 mRNA, but neither finding establishes that BACE1 protein increases during aging. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Boissonneault et al. 2009

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Premisecitation

    BACE1 expression is elevated in cortices of AD patients compared to age-matched, non-demented controls.

    “Post-mortem analyses revealed that BACE1 expression is elevated in cortices of AD patients compared to the age-matched, non-demented controls (Fukumoto et al. 2002, Yang et al. 2003, Hebert et al. 2008, Ahmed et al. 2010).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Fukumoto et al. 2002

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Yang et al. 2003 source
    • cites Hebert et al. 2008 source

      The Results report significantly higher BACE1 protein in anterior temporal cortex samples from 34 sporadic AD patients than from 21 controls, driven by 11 patients with particularly high levels. The paper calls five controls in an earlier miRNA pilot study age-matched, but our copy does not establish that the 21 controls in the BACE1 comparison were age-matched and non-demented. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    An extensive network of multiple miRNAs may regulate BACE1 expression in a coordinated manner.

    “So far, several miRNAs have been identified as regulators of BACE1 expression (Hebert et al. 2008, Zong et al. 2011, Zhu et al. 2012, Fang et al. 2012, Wang et al. 2008b, Boissonneault et al. 2009, Long et al. 2014), suggesting that an extensive network of multiple miRNAs may regulate BACE1 expression in a coordinated manner.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Hebert et al. 2008 source
    • cites Zong et al. 2011 source
    • cites Zhu et al. 2012 source
  • Classified as probably not a substantial claim. 32
  • May combine two claims. 9

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In humans, aging processes such as proinflammation and cognitive decline begin in midlife.

    “Interestingly, emerging evidence also suggests that in humans the aging processes, such as proinflammation and cognitive decline, begin in midlife(Ferrucci et al. 2005, Belsky et al. 2015).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Ferrucci et al. 2005 source

      The Abstract and Discussion (page numbers unavailable) report that several inflammatory markers increase with age in humans, supporting the proinflammation portion. The paper does not establish that this process begins in midlife; its Discussion mentions dementia but does not examine when cognitive decline begins. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Belsky et al. 2015 source

      The paper’s Discussion reports age-related biomarker changes from ages 26 to 38, and its brain-aging section reports cognitive decline associated with older Biological Age at age 38. This supports aging and cognitive decline being detectable by midlife, but the passages do not establish proinflammation specifically or that these processes begin in midlife rather than earlier. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Both oxidative stress and inflammation increase BACE1 expression.

    “Interestingly, several studies have suggested that both oxidative stress and inflammation increase BACE1 expression (Chami & Checler 2012, Rossner et al. 2006, Tamagno et al. 2012).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Chami & Checler 2012 source
    • cites Rossner et al. 2006

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Tamagno et al. 2012 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Genome wide expression profiling studies have identified several genes and biological pathways affected by aging.

    “Genome wide expression profiling studies have identified several genes and biological pathways affected by aging (Bishop et al. 2010, Lopez-Otin et al. 2013, Kenyon 2010, Yankner et al. 2008).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Bishop et al. 2010 source
    • cites Lopez-Otin et al. 2013 source
    • cites Kenyon 2010 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Only a small population of miRNAs accounts for a majority of miRNA pool in the brain.

    “Previous studies have shown that only a small population of miRNAs accounts for a majority of miRNA pool in the brain (Shin et al. 2010, Hu et al. 2011, Landgraf et al. 2007, Berezikov et al. 2006).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Shin et al. 2010 source

      The Results section, “MicroRNA-directed Cleavage in HeLa Cells and Human brain” (page unavailable), says that brain miRNAs were identified by small-RNA sequencing, but does not report what fraction of the miRNA pool is made up by a small number of miRNAs. Searches for brain miRNA abundance and the proportion of total miRNA reads found no passage addressing that distribution. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites Hu et al. 2011

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Landgraf et al. 2007 source

  • Classified as probably not a substantial claim.

    Premisecitation

    AD pathology, such as cerebral Aβ accumulation, probably begins one to two decades before onset of clinical symptoms.

    “Growing evidence suggests that AD pathology, such as cerebral Aβ accumulation, probably begins one to two decades before onset of clinical symptoms (Holtzman et al. 2011, Perrin et al. 2009).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Holtzman et al. 2011 source
    • cites Perrin et al. 2009 source

  • Classified as probably not a substantial claim.

    Premisecitation

    BACE1 has a rate-limiting role in Aβ generation from APP.

    “Given the rate-limiting role of BACE1 in Aβ generation from APP, strategies to lower cerebral Aβ levels by inhibiting BACE1 have been extensively pursued as AD therapeutics (De Strooper et al. 2010).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites De Strooper et al. 2010 source

      In β-Secretase > Biological activity (page unavailable), the review says BACE1 is the main, if not the only, β-secretase in the brain and that mice lacking BACE1 have no cerebral Aβ. β-Secretase > Drug development (page unavailable) describes BACE1 inhibitors developed to lower cerebral Aβ. These passages support BACE1’s importance and the therapeutic strategy, but do not establish that its action is specifically rate-limiting. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several miRNAs have been identified as regulators of BACE1 expression.

    “So far, several miRNAs have been identified as regulators of BACE1 expression (Hebert et al. 2008, Zong et al. 2011, Zhu et al. 2012, Fang et al. 2012, Wang et al. 2008b, Boissonneault et al. 2009, Long et al. 2014), suggesting that an extensive network of multiple miRNAs may regulate BACE1 expression in a coordinated manner.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Hebert et al. 2008 source
    • cites Zong et al. 2011 source
    • cites Zhu et al. 2012 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    miR-186 suppresses P2RX7 in epithelial cancer cells.

    “Moreover, miR-186 suppresses purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7) in epithelial cancer cells (Zhou et al. 2008).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Zhou et al. 2008 source

  • May combine two claims.

    Premisecitation

    Complete loss of Bace1 in mice leads to schizophrenia-like phenotypes and deficits in cognitive function, mossy fiber long-term potentiation (LTP), synaptic plasticity, and axon guidance.

    “Complete loss of Bace1 in mice are known to lead to schizophrenia-like phenotypes and deficits in cognitive function, mossy fiber long-term potentiation (LTP), synaptic plasticity, and axon guidance (Savonenko et al. 2008, Wang et al. 2008a, Petrus & Lee 2014, Hitt et al. 2012, Rajapaksha et al. 2011).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Savonenko et al. 2008

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Wang et al. 2008a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Petrus & Lee 2014 source

      The Results and Discussion (page unavailable) report that BACE1 knockout mice lack experience-dependent homeostatic synaptic plasticity in visual cortex, supporting the synaptic-plasticity part of the sentence. Our copy does not report schizophrenia-like phenotypes, cognitive deficits, mossy fiber LTP deficits, or axon-guidance deficits in these mice; it mentions axon myelination, which is different from guidance. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    BACE1 expression is up-regulated by oxidative stress and inflammation.

    “Although BACE1 expression has been known to be up-regulated by oxidative stress and inflammation (Chami & Checler 2012, Rossner et al. 2006, Tamagno et al. 2012), our data suggest that miR-186 does not mediate the BACE1 induction by those aging-associated stresses.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Chami & Checler 2012 source
    • cites Rossner et al. 2006

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Tamagno et al. 2012 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    miR-186 level is decreased in the white matter of the temporal cortex in AD brain.

    “Interestingly, one report showed that miR-186 level is decreased in the white matter of the temporal cortex in AD brain (Wang et al. 2011).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Wang et al. 2011 source

      The Abstract reports that miR-212 is downregulated in AD white matter, but does not identify miR-186. Searches of the indexed Results and Discussion for miR-186 and decreased expression in white matter found no passage establishing the claimed change. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    BACE1 has multiple substrates involved in various processes in the brain.

    “BACE1 has multiple substrates involved in various processes in the brain (Vassar et al. 2009).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Vassar et al. 2009 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    P2RX7 mediates apoptosis by activating mitochondrial caspase 9 pathway in human cervical endothelial cells.

    “P2RX7 mediates apoptosis by activating mitochondrial caspase 9 pathway in human cervical endothelial cells (Wang et al. 2004).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Wang et al. 2004 source

      The section “Estrogen blocks BzATP activation of caspase-9 and caspase-3” reports that P2X7 receptor activation induces apoptosis mainly through the mitochondrial pathway and that BzATP activates caspase-9. However, the cells studied are human cervical epithelial cells, not endothelial cells; the claim's cell type is unsupported. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Multiple miRNAs are dysregulated in the affected regions of AD brains.

    “Recent miRNA profiling studies showed that multiple miRNAs are dysregulated in the affected regions of AD brains (Lau et al. 2013, Hebert et al. 2008, Wang et al. 2011, Delay et al. 2012, Cogswell et al. 2008, Lukiw 2007).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Lau et al. 2013 source
    • cites Hebert et al. 2008 source
    • cites Wang et al. 2011 source

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    miR-186 is up-regulated in the grey matter of the prefrontal cortex in AD brains.

    “On the other hand, another study reported that miR-186 is up-regulated in the grey matter of the prefrontal cortex in AD brains (Lau et al. 2013).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Lau et al. 2013 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The sequences of pre-mir-186 and mature miR-186 are well conserved in mammals, such as human, mouse, and rat.

    “The sequences of precursor microRNA-186 (pre-mir-186) and mature microRNA-186 (miR-186) are well conserved in mammals, such as human, mouse, and rat (Fig. 3A).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    miR-186 is expressed throughout different organs.

    “miR-186 is expressed throughout different organs (Fig. 2A).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Both miR-186 and BACE1 are expressed in the brain and are particularly enriched in neurons.

    “Both miR-186 and BACE1 are expressed in the brain and are particularly enriched in neurons (Fig. 2) (Vassar et al. 1999).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Vassar et al. 1999 source

  • Classified as probably not a substantial claim.

    Premisecitation

    miRNAs regulate gene expression by binding to target mRNAs, leading to translational repression and/or degradation of target mRNAs.

    “Genome-encoded small non-coding miRNAs regulate gene expression by binding to their target messenger RNAs (mRNAs), leading to translational repression and/or degradation of their target mRNAs (Huntzinger & Izaurralde 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Huntzinger & Izaurralde 2011

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Premisecitation

    Aβ is generated through sequential cleavages of APP by BACE1 and γ-secretase complex.

    “Aβ is generated through sequential cleavages of amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase complex (De Strooper 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites De Strooper 2010 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The purity of primary cells was monitored by neuron-specific βIII-tub and astrocyte-specific GFAP.

    “The purity of primary cells was monitored by neuron-specific tubulin, beta 3 class III (βIII-tub) and astrocyte-specific glial fibrillary acidic protein (GFAP).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Aging is accompanied with the increase of oxidative stress and inflammation in the brain.

    “Mounting evidence has shown that aging is accompanied with the increase of oxidative- stress and inflammation in the brain (Franceschi et al. 2000, Finkel & Holbrook 2000, Balaban et al. 2005, Lee et al. 2000, Guest et al. 2014, Lynch 2010).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Franceschi et al. 2000 source
    • cites Finkel & Holbrook 2000

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Balaban et al. 2005 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Aβ secretion experiments included duplicates or triplicates and were repeated independently twice or more.

    “Experiments included duplicates or triplicates and were repeated independently twice or more.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Overexpression of miR-186 suppresses BACE1 expression by inhibiting translation as well as destabilizing mRNA.

    “Taken together, these data demonstrate that overexpression of miR-186 suppresses BACE1 expression by inhibiting translation as well as destabilizing mRNA.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Dysregulation of miRNAs may contribute to the onset and/or progression of various diseases by regulating disease-associated genes.

    “Growing evidence suggests that dysregulation of miRNAs may contribute to the onset and/or progression of various diseases by regulating disease-associated genes (Delay et al. 2012, Schonrock et al. 2012, Esteller 2011).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Delay et al. 2012 source
    • cites Schonrock et al. 2012

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Esteller 2011 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Each luciferase experiment was independently repeated twice or more in duplicate or triplicate.

    “Each experiment was independently repeated twice or more in duplicate or triplicate.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Data sets were tested for equal variance and normality before parametric testing.

    “To determine the statistical significance (*p<0.05, **p<0.01, ***p<0.001), we first tested whether our data sets passed the equal variance test (Levene Median test) and normality test (Kolmogorov-Smirnov test) (SigmaStat 3.5).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All procedures with animals followed guidelines approved by the Animal Studies Committee at Washington University and Mayo Clinic College of Medicine.

    “All procedures with animals followed the guidelines approved by the Animal Studies Committee at Washington University and Mayo Clinic College of Medicine.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Endogenous Gapdh, U6, or sno202 was used as normalization controls for mRNAs and miRNAs.

    “Endogenous Gapdh, U6, or sno202 was used as normalization controls for mRNAs and miRNAs, as indicated.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Dysregulation of multiple miRNAs regulating BACE1 may be involved in the induction of BACE1 in AD brains and thereby exacerbating Aβ-associated pathology in AD patients.

    “Although the role of miR-186 in AD pathogenesis remains elusive, dysregulation of multiple miRNAs regulating BACE1 may be involved in the induction of BACE1 in AD brains and thereby exacerbating Aβ-associated pathology in AD patients.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pharmacological inhibition of P2RX7 reduces hippocampal amyloid plaques in an Aβ-amyloidosis mouse model.

    “However, pharmacological inhibition of P2RX7 reduces hippocampal amyloid plaques in an Aβ-amyloidosis mouse model (Diaz-Hernandez et al. 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Diaz-Hernandez et al. 2012

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    P2RX7 levels are elevated in AD brains.

    “Intriguingly, P2RX7 levels are elevated in AD brains (McLarnon et al. 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites McLarnon et al. 2006 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    P2RX7 increases α-cleavage of APP in vitro.

    “P2RX7 is known to increase α-cleavage of APP in vitro (Delarasse et al. 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Delarasse et al. 2011

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    miR-186 may represent a novel therapeutic target for AD.

    “Although the effect of miR-186 on P2RX7 in the brain remains elusive, these findings, together with our results, suggest miR-186 may represent a novel therapeutic target for AD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Premisecitation

    Aging is broadly defined by a progressive decline in physiological functions, accompanied with increase of oxidative stress and inflammation in the brain.

    “Aging is broadly defined by a progressive decline in physiological functions, accompanied with increase of oxidative stress and inflammation in the brain (Franceschi et al. 2000, Finkel & Holbrook 2000, Balaban et al. 2005, Lee et al. 2000, Guest et al. 2014, Lynch 2010, Lopez-Otin et al. 2013).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Franceschi et al. 2000 source
    • cites Finkel & Holbrook 2000

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Balaban et al. 2005 source
35 of 35

  • The paper relies on this without support.

    Little is known about the molecular mechanism of how BACE1 expression is regulated by the aging process.

    “Nonetheless, little is known about the molecular mechanism of how BACE1 expression is regulated by the aging process.”

  • The paper relies on this without support.

    Aging is the most prominent risk factor for AD.

    “Aging is the most prominent risk factor for AD.”
2 of 2

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Kim, J., Yoon, H., Chung, D., Brown, J. L., Belmonte, K. C., & Kim, J.
Affiliations
  • Department of Neuroscience Mayo Clinic College of Medicine Jacksonville Florida USA
  • Mayo Clinic (US)
ORCID
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2016-03-30
Volume
137
Issue
3
Pages
436-445
ISSN
  • 0022-3042 (ISSN-L)
  • 1471-4159
DOI
10.1111/jnc.13507
PMC
PMC4837067
OpenAlex
W2213477888
Semantic Scholar
cc6adf5546dfe748eea5f37ed71ec6d30583d8b3
Cited by
102
References
86
Citations by year
2026: 6 · 2025: 9 · 2024: 9 · 2023: 13 · 2022: 11 · 2021: 11 · 2020: 9 · 2019: 14 · 2018: 7 · 2017: 10 · 2016: 3
FWCI
4.29
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Journal of Neurochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institutes of Health (NS069329, AG016574, AG005681)
  • BrightFocus Foundation (A2012421)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
miR-186, BACE1, Alzheimer's disease, brain aging, amyloid-beta, microRNA regulation, 3' UTR targeting, amyloid precursor protein, cortical neurons, mouse brain
MeSH terms
Aging, Alzheimer Disease, Animals, Base Sequence, Brain Chemistry, Cerebral Cortex, Gene Expression Regulation, Mice, Inbred C57BL, Molecular Sequence Data, Mutation, Neurons, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, 3' Untranslated Regions, MicroRNAs, Mice, Amyloid Precursor Protein Secretases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-17.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review