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Cited by 23Cholesterol and Lipid MetabolismMicroRNA in disease regulationNeuroinflammation and Neurodegeneration Mechanisms

MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease

Open access
Yoon, Hyejin, Flores, Luis F., Kim, Jungsu·2016·Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
DOI 10.1016/j.bbalip.2016.04.020PMC PMC5097035
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Abstract

Cholesterol is important for various neuronal functions in the brain. Brain has elaborate regulatory mechanisms to control cholesterol metabolism that are distinct from the mechanisms in periphery. Interestingly, dysregulation of the cholesterol metabolism is strongly associated with a number of neurodegenerative diseases. MicroRNAs are short non-coding RNAs acting as post-transcriptional gene regulators. Recently, several microRNAs are demonstrated to be involved in regulating cholesterol metabolism in the brain. This article reviews the regulatory mechanisms of cellular cholesterol homeostasis in the brain. In addition, we discuss the role of microRNAs in brain cholesterol metabolism and their potential implications for the treatment of Alzheimer's disease. This article is part of a special issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes brain cholesterol homeostasis and evidence that microRNAs regulate cholesterol/ceramide metabolism and amyloid-β production, with therapeutic implications for Alzheimer’s disease. It highlights ABCA1-targeting microRNAs (miR-106b-5p, miR-758-5p, and miR-33a) and discusses barriers such as target prediction and brain delivery.

Key findings

  • The brain contains almost 25% of total body cholesterol and synthesizes cholesterol in situ because lipoprotein-mediated peripheral cholesterol transport is blocked by the blood-brain barrier; astrocytes synthesize cholesterol at a higher rate than neurons and transfer excess cholesterol to neurons.
  • MicroRNAs are short non-coding RNAs approximately 22 nucleotides in length; it has been estimated that 60% of human protein-encoding genes contain at least one conserved miRNA-binding site.
  • In brain-relevant studies, miR-137 and miR-181c decrease SPTLC1 and ceramide in primary astrocytes, while miR-9 and miR-29a/b-1 decrease SPTLC2 and ceramide; inhibition of these miRNAs increased SPTLC levels and Aβ production.
  • ABCA1 is targeted by miR-106b-5p, miR-758-5p, and miR-33a; miR-106b-5p reduces ABCA1, decreases cholesterol efflux, and increases Aβ secretion, while miR-33 overexpression decreases ABCA1 and impairs cholesterol efflux in neuronal and glial cells and increases extracellular Aβ; genetic and pharmacologic inhibition of miR-33 decreased cortical Aβ levels.

Methods

  • Narrative review synthesizing literature on peripheral versus CNS cholesterol homeostasis, miRNA biogenesis, and miRNA regulation of brain lipid metabolism.
  • No primary data, sample, or statistical analysis are reported; cited evidence includes cell models, mouse models, and human clinical trial data.
  • Main analysis is qualitative synthesis of cited findings and proposed mechanisms linking miRNAs to cholesterol metabolism and Aβ metabolism.

Limitations

  • Stated: one miRNA can regulate multiple target genes, so other targets must be considered; target prediction algorithms overestimate targets, often identify false positives, and show no strong overlap, requiring wet-lab validation and systems biology approaches.
  • Stated: delivery across the blood-brain barrier is a major obstacle for clinical application; intrathecal antisense oligonucleotide injection and other delivery methods are promising but require further preclinical and clinical studies, and several miRNA effects (e.g., miR-758-5p, miR-106b-5p, miR-137/181c) need in vivo validation.
  • Evident: as a narrative review, it does not use systematic search/selection criteria or quantitative synthesis, so conclusions depend on the cited studies.

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

Integrity signals

Registry

Crossref · 10.1016/j.bbalip.2016.04.020

Cites

149 of 149 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

50 of 68 cited sources checked · 24 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Alterations in cholesterol level or key cholesterol regulators lead to changes in Aβ metabolism.

    “Multiple studies have demonstrated that the alterations in cholesterol level or key cholesterol regulators lead to change in Aβ metabolism [51, 59-61].”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [51] Kim J Basak JM Holtzman DM The role of apolipoprotein E in Alzheimer's disease Neuron 2009 63 287 303 19679070 PMC3044446 source

      The ABCA1 section (page unavailable) identifies ABCA1 as a cholesterol transporter and reports that altering it changes Aβ load and deposition in mouse models. This supports the claim about a key cholesterol regulator, but the passages do not establish that changing cholesterol levels themselves changes Aβ metabolism. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [59] Koldamova R Fitz NF Lefterov I The role of ATP-binding cassette transporter A1 in Alzheimer's disease and neurodegeneration Biochim Biophys Acta 2010 1801 824 830 20188211 PMC3712769 source
    • cites [60] Sun JH Yu JT Tan L The role of cholesterol metabolism in Alzheimer's disease Mol Neurobiol 2015 51 947 965 24838626 source
    • cites [61] Ghribi O Larsen B Schrag M Herman MM High cholesterol content in neurons increases BACE, beta-amyloid, and phosphorylated tau levels in rabbit hippocampus Exp Neurol 2006 200 460 467 16696972 source
  • Premisecitation

    ABCA1 induction decreases Aβ levels in cells by inhibiting both β- and γ-cleavage of APP.

    “Koldamova et al. and Sun et al. reported that ABCA1 induction decreases Aβ levels in cells by inhibiting both β- and γ-cleavage of APP [62-64].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [62] Koldamova RP Lefterov IM Ikonomovic MD Skoko J Lefterov PI Isanski BA DeKosky ST Lazo JS 22R-hydroxycholesterol and 9-cis-retinoic acid induce ATP-binding cassette transporter A1 expression and cholesterol efflux in brain cells and decrease amyloid beta secretion J Biol Chem 2003 278 13244 13256 12547833 source

      The APP-processing results report reduced Aβ secretion in cells treated with LXR/RXR ligands, alongside ABCA1 induction. They do not establish that ABCA1 induction inhibits both β- and γ-cleavage of APP; the paper says APP processing may also be affected through a mechanism independent of ABCA1-mediated cholesterol depletion. Section labels are available in our copy, but page numbers are not. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [63] Koldamova RP Lefterov IM Staufenbiel M Wolfe D Huang S Glorioso JC Walter M Roth MG Lazo JS The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease J Biol Chem 2005 280 4079 4088 15557325 source

      The ABCA1 Overexpression section and Figure 4 report reduced Aβ secretion from cells overexpressing ABCA1. The APP23 Mice results report a lower ratio of β- to α-cleavage products after LXR-ligand treatment, but they do not establish that ABCA1 induction inhibits both β- and γ-cleavage in cells. The claimed two-cleavage mechanism is therefore not supported by this paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [64] Sun Y Yao J Kim TW Tall AR Expression of liver X receptor target genes decreases cellular amyloid beta peptide secretion J Biol Chem 2003 278 27688 27694 12754201 source
  • Premisecitation

    Most cholesterol in the CNS is synthesized in situ because the blood-brain barrier blocks transport of peripheral lipoprotein cholesterol to the brain.

    “Most cholesterol in CNS is synthesized in situ, because the transport of lipoprotein-mediated peripheral cholesterol to brain is blocked by BBB [29, 30].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [29] Dietschy JM Turley SD Thematic review series: brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal J Lipid Res 2004 45 1375 1397 15254070 source
    • cites [30] Wang H Eckel RH What are lipoproteins doing in the brain? Trends Endocrinol Metab 2014 25 8 14 24189266 PMC4062975 source

      The “Major Differences between Lipoproteins in Plasma vs. in the Brain” section says the BBB necessitates local synthesis to maintain brain cholesterol homeostasis, supporting the main point. But it also says some circulating HDL enters the brain, and the “Scavenger receptor class B type 1 (SR-BI)” section describes uptake of HDL-associated cholesterol ester after HDL crosses the BBB. The claim’s categorical statement that the BBB blocks peripheral lipoprotein-mediated cholesterol transport is therefore too strong; page numbers were not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    miR-33 increases extracellular Aβ levels in mouse and human neuronal cells.

    “miR-33 increased extracellular Aβ levels in mouse and human neuronal cells.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [127] Kim J Yoon H Horie T Burchett JM Restivo JL Rotllan N Ramirez CM Verghese PB Ihara M Hoe HS Esau C Fernandez-Hernando C Holtzman DM Cirrito JR Ono K microRNA-33 Regulates ApoE Lipidation and Amyloid-beta Metabolism in the Brain J Neurosci 2015 35 14717 14726 26538644 PMC4635126 source

      The section on Aβ secretion and clearance reports increased secreted Aβ after miR-33 transfection in mouse N2a cells, with similar results in human H4 cells. The human cells are identified as neuroglioma cells, not neuronal cells, so the claim overstates that cell-type detail. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    Pharmacological inhibition of miR-33 significantly increases ABCA1 level.

    “pharmacological inhibition of miR-33 significantly increased ABCA1 level [127, 128].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [127] Kim J Yoon H Horie T Burchett JM Restivo JL Rotllan N Ramirez CM Verghese PB Ihara M Hoe HS Esau C Fernandez-Hernando C Holtzman DM Cirrito JR Ono K microRNA-33 Regulates ApoE Lipidation and Amyloid-beta Metabolism in the Brain J Neurosci 2015 35 14717 14726 26538644 PMC4635126 source
    • cites [128] Jan A Karasinska JM Kang MH de Haan W Ruddle P Kaur A Connolly C Leavitt BR Sorensen PH Hayden MR Direct intracerebral delivery of a miR-33 antisense oligonucleotide into mouse brain increases brain ABCA1 expression. Neurosci Lett 2015 598 66 72 [Corrected] 25957561 source
  • May combine two claims. 13
  • Classified as probably not a substantial claim. 2

  • May combine two claims.

    Premisecitation

    Treatment with LXR/RXR agonists increases levels of ABCA1 and APOE and decreases amyloid deposition in APP overexpressing cells and mice.

    “Several studies demonstrated that treatment of LXR/RXR agonists increase the levels of ABCA1 and APOE and decrease amyloid deposition in APP overexpressing cells and mice [73-77].”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [73] Donkin JJ Stukas S Hirsch-Reinshagen V Namjoshi D Wilkinson A May S Chan J Fan J Collins J Wellington CL ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice J Biol Chem 2010 285 34144 34154 20739291 PMC2962513 source
    • cites [74] Cramer PE Cirrito JR Wesson DW Lee CY Karlo JC Zinn AE Casali BT Restivo JL Goebel WD James MJ Brunden KR Wilson DA Landreth GE ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models Science 2012 335 1503 1506 22323736 PMC3651582 source

      The Abstract (passage 6; page unavailable) reports increased apoE and ABCA1 expression and reduced Aβ plaques after short-term bexarotene treatment in APP/PS1 mice. It also reports increased expression in treated primary microglia and astrocytes (passage 2), but does not identify these as APP-overexpressing cells or show decreased amyloid deposition in them. Plaque burden was unchanged after three months of treatment in APP/PS1 mice (passage 5). (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [75] Fitz NF Cronican AA Lefterov I Koldamova R Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models” Science 2013 340 924 c PMC4086452 23704552 source

      The paper reports increased ABCA1 and APOE protein levels after bexarotene treatment, but its findings contradict the attributed decrease in amyloid deposition. In the section labeled Abstract, it reports no significant difference in plaques between treated and control APP/E3 or APP/E4 mice, while distinguishing that result from a decrease in interstitial-fluid Aβ. It does not report a cell experiment. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [76] Tesseur I Lo AC Roberfroid A Dietvorst S Van Broeck B Borgers M Gijsen H Moechars D Mercken M Kemp J D'Hooge R De Strooper B Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models” Science 2013 340 924 e 23704554 source
    • cites [77] Veeraraghavalu K Zhang C Miller S Hefendehl JK Rajapaksha TW Ulrich J Jucker M Holtzman DM Tanzi RE Vassar R Sisodia SS Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models” Science 2013 340 924 f 23704555 source

  • May combine two claims.

    Premisecitation

    Astrocytes synthesize cholesterol at a higher rate than neurons and transfer excess cholesterol to neurons.

    “strong evidence suggests that astrocytes synthesize cholesterol at a higher rate than neurons and transfer their excess cholesterol to neurons [38, 40].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [38] Funfschilling U Saher G Xiao L Mobius W Nave KA Survival of adult neurons lacking cholesterol synthesis in vivo BMC Neurosci 2007 8 1 17199885 PMC1769390 source

      The Background describes astrocytes as presumed net cholesterol producers, and the Discussion says adult neurons may rely on glial cholesterol, with astrocytes among the likely suppliers. The paper does not establish that astrocytes synthesize cholesterol at a higher rate than neurons or that the cholesterol they supply is excess. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [40] Hayashi H Lipid metabolism and glial lipoproteins in the central nervous system Biol Pharm Bull 2011 34 453 461 21467629 source

      Section 1 (Lipid Homeostasis in the CNS; page not available) says cholesterol synthesis after myelination occurs mainly in astrocytes, while neurons synthesize it inefficiently and obtain it from astrocytes. The paper supports transfer to neurons, but does not describe the cholesterol transferred as excess cholesterol in astrocytes. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

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

    Premisecitation

    APOE4 genotype is the strongest genetic risk factor for AD.

    “APOE4 genotype is the strongest genetic risk factor for AD”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [51] Kim J Basak JM Holtzman DM The role of apolipoprotein E in Alzheimer's disease Neuron 2009 63 287 303 19679070 PMC3044446 source
    • cites [52] Kim J Yoon H Basak J Apolipoprotein E in synaptic plasticity and Alzheimer's disease: potential cellular and molecular mechanisms Mol Cells 2014 37 767 776 25358504 PMC4255096 source

      The ALZHEIMER’S DISEASE section identifies the APOE ε4 allele as the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD). The citing sentence says AD without that qualification, extending the statement beyond the population specified in the paper’s body text. No page number is available in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Both genetic and pharmacologic inhibition of miR-33 decreases cortical Aβ levels.

    “Both genetic and pharmacologic inhibition of miR-33 decreased cortical Aβ levels. [127].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [127] Kim J Yoon H Horie T Burchett JM Restivo JL Rotllan N Ramirez CM Verghese PB Ihara M Hoe HS Esau C Fernandez-Hernando C Holtzman DM Cirrito JR Ono K microRNA-33 Regulates ApoE Lipidation and Amyloid-beta Metabolism in the Brain J Neurosci 2015 35 14717 14726 26538644 PMC4635126 source

  • May combine two claims.

    Premisecitation

    miR-106b-5p directly targets the 3' UTR of ABCA1 and significantly decreases ABCA1 protein level in a neuronal cell line and in fully differentiated primary hippocampal neurons.

    “miR-106b-5p directly targets the 3’ UTR of ABCA1 and significantly decreases the ABCA1 protein level in a neuronal cell line as well as in fully differentiated primary hippocampal neurons [116].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [116] Kim J Yoon H Ramirez CM Lee SM Hoe HS Fernandez-Hernando C MiR-106b impairs cholesterol efflux and increases Abeta levels by repressing ABCA1 expression Exp Neurol 2012 235 476 483 22119192 PMC3328628 source

  • May combine two claims.

    Premisecitation

    ABCA1 gene ablation in mice decreases APOE lipidation and levels and increases Aβ accumulation in APP transgenic mouse models.

    “ABCA1 gene ablation in mice decreased APOE lipidation and levels and increased Aβ accumulation in APP transgenic mouse models.”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [63] Koldamova RP Lefterov IM Staufenbiel M Wolfe D Huang S Glorioso JC Walter M Roth MG Lazo JS The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease J Biol Chem 2005 280 4079 4088 15557325 source

      The Discussion (page unavailable) reports markedly lower brain and cerebrospinal-fluid apoE levels in ABCA1-knockout mice, but its statement about abnormal lipidation concerns HDL, not specifically apoE. It does not report increased Aβ accumulation after ABCA1 ablation in APP-transgenic mice; instead, it says the effect of ABCA1 loss on the Alzheimer’s disease phenotype is difficult to predict. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [66] Hirsch-Reinshagen V Maia LF Burgess BL Blain JF Naus KE McIsaac SA Parkinson PF Chan JY Tansley GH Hayden MR Poirier J Van Nostrand W Wellington CL The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease J Biol Chem 2005 280 43243 43256 16207707 source

      The ‘Deficiency of ABCA1 Reduces Soluble ApoE Levels in Vivo’ section reports lower soluble apoE in both APP-transgenic models, and the Discussion describes apoE in ABCA1-deficient mice as poorly lipidated. The ‘ABCA1 Deficiency Increases Aβ Deposition in Tg-SwDI/B’ section reports increased Aβ deposition in Tg-SwDI/B mice, but no significant increase in APP/PS1 mice; the claim overgeneralizes the accumulation finding to both models. Page numbers were not available in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [67] Koldamova R Staufenbiel M Lefterov I Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice J Biol Chem 2005 280 43224 43235 16207713 source
    • cites [68] Wahrle SE Jiang H Parsadanian M Hartman RE Bales KR Paul SM Holtzman DM Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease J Biol Chem 2005 280 43236 43242 16207708 source
    • cites [69] Wahrle SE Jiang H Parsadanian M Kim J Li A Knoten A Jain S Hirsch-Reinshagen V Wellington CL Bales KR Paul SM Holtzman DM Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease J Clin Invest 2008 118 671 682 18202749 PMC2200302 source

  • May combine two claims.

    Premisecitation

    Reduction of ABCA1 levels by miR-106b-5p is sufficient to decrease cellular cholesterol efflux and increase Aβ secretion.

    “The reduction of ABCA1 levels by miR-106b-5p was sufficient to decrease cellular cholesterol efflux and increase Aβ secretion.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [116] Kim J Yoon H Ramirez CM Lee SM Hoe HS Fernandez-Hernando C MiR-106b impairs cholesterol efflux and increases Abeta levels by repressing ABCA1 expression Exp Neurol 2012 235 476 483 22119192 PMC3328628 source

  • May combine two claims.

    Premisecitation

    Inhibition of miRNAs that regulate SPTLC increases SPTLC levels, leading to more Aβ production.

    “Conversely, inhibition of those miRNAs increased SPTLC levels, leading to more Aβ production.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [112] Geekiyanage H Chan C MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid beta, novel targets in sporadic Alzheimer's disease J Neurosci 2011 31 14820 14830 21994399 PMC3200297 source

  • May combine two claims.

    Premisecitation

    Current target prediction algorithms often identify many false positive target genes and there is no strong overlap in predicted target gene list among prediction algorithms.

    “current target prediction algorithms often identify many false positive target genes and there is no strong overlap in the predicted target gene list among prediction algorithms [138-141].”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [138] Didiano D Hobert O Perfect seed pairing is not a generally reliable predictor for miRNA-target interactions Nat Struct Mol Biol 2006 13 849 851 16921378 source
    • cites [139] Kertesz M Iovino N Unnerstall U Gaul U Segal E The role of site accessibility in microRNA target recognition Nat Genet 2007 39 1278 1284 17893677 source
    • cites [140] Chi SW Hannon GJ Darnell RB An alternative mode of microRNA target recognition Nat Struct Mol Biol 2012 19 321 327 22343717 PMC3541676 source

      The Abstract reports that seed-based target-identification strategies have false-positive prediction rates of about 40–66%, supporting the first part of the claim. It does not compare predicted gene lists across algorithms or say that their overlap is weak. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [141] Saetrom P Biesinger J Li SM Smith D Thomas LF Majzoub K Rivas GE Alluin J Rossi JJ Krontiris TG Weitzel J Daly MB Benson AB Kirkwood JM O'Dwyer PJ Sutphen R Stewart JA Johnson D Larson GP A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis Cancer Res 2009 69 7459 7465 19738052 PMC2747041 source

      The Results section (‘Multiple HapMap SNPs map to putative miRNA target sites’; page unavailable) acknowledges false-positive target-site predictions when explaining the choice of 7mer seed sites. It does not establish that algorithms often predict many false-positive target genes, and our copy does not report how strongly target lists from different algorithms overlap. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    miR-758-5p overexpression significantly decreases ABCA1 protein levels and cellular cholesterol efflux in cells, whereas inhibition of endogenous miR-758 causes opposite effects.

    “miR-758-5p overexpression significantly decreased ABCA1 protein levels and cellular cholesterol efflux in cells, whereas inhibition of endogenous miR-758 caused the opposite effects.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [118] Ramirez CM Davalos A Goedeke L Salerno AG Warrier N Cirera-Salinas D Suarez Y Fernandez-Hernando C MicroRNA-758 regulates cholesterol efflux through posttranscriptional repression of ATP-binding cassette transporter A1 Arterioscler Thromb Vasc Biol 2011 31 2707 2714 21885853 PMC3298756 source

      The Results section on neuroglioma cells reports that miR-758 overexpression decreased ABCA1 protein and cholesterol efflux to ApoA1, while inhibition increased both. Our copy calls the molecule miR-758, not miR-758-5p, so it does not establish the claim's strand-specific identification. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    ABCA1 overexpression or LXR/RXR agonist treatment decreases amyloid deposition in APP transgenic mouse models.

    “ABCA1 overexpression or LXR/RXR agonist treatment decreased amyloid deposition [66-69].”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [66] Hirsch-Reinshagen V Maia LF Burgess BL Blain JF Naus KE McIsaac SA Parkinson PF Chan JY Tansley GH Hayden MR Poirier J Van Nostrand W Wellington CL The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease J Biol Chem 2005 280 43243 43256 16207707 source

      The paper reports that an LXR ligand reduced Aβ40 and Aβ42 levels in APP23 mice, which supports part of the treatment claim, but it does not say that the treatment reduced amyloid deposition. Its own study examines ABCA1 deficiency, not overexpression, and the cited passages do not report an RXR-agonist experiment. The relevant passages are labeled Abstract in our copy; no page number is available. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [67] Koldamova R Staufenbiel M Lefterov I Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice J Biol Chem 2005 280 43224 43235 16207713 source
    • cites [68] Wahrle SE Jiang H Parsadanian M Hartman RE Bales KR Paul SM Holtzman DM Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease J Biol Chem 2005 280 43236 43242 16207708 source

      The Discussion reports that an LXR agonist lowered brain Aβ40 and Aβ42 levels in APP23 mice before plaque deposition; it does not report decreased amyloid deposition from that treatment. It describes decreased deposition from increasing ABCA1 as a prediction that still needs direct testing, while this paper studied ABCA1 deletion. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [69] Wahrle SE Jiang H Parsadanian M Kim J Li A Knoten A Jain S Hirsch-Reinshagen V Wellington CL Bales KR Paul SM Holtzman DM Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease J Clin Invest 2008 118 671 682 18202749 PMC2200302 source

      The Introduction reports that ABCA1 overexpression reduced amyloid deposition in PDAPP mice, an APP transgenic model. The Discussion says LXR agonists affect Aβ levels, but does not establish that LXR/RXR agonist treatment decreased amyloid deposition in these mice. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Overexpression of miR-33 decreases ABCA1 levels and impairs cholesterol efflux in neuronal and glial cells.

    “overexpression of miR-33 decreased ABCA1 levels and impaired cholesterol efflux in neuronal and glial cells [127].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [127] Kim J Yoon H Horie T Burchett JM Restivo JL Rotllan N Ramirez CM Verghese PB Ihara M Hoe HS Esau C Fernandez-Hernando C Holtzman DM Cirrito JR Ono K microRNA-33 Regulates ApoE Lipidation and Amyloid-beta Metabolism in the Brain J Neurosci 2015 35 14717 14726 26538644 PMC4635126 source

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

    Premisecitation

    Several small molecules have been identified to modulate miRNAs.

    “In addition, several small molecules have been identified to modulate miRNAs [148].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [148] Velagapudi SP Vummidi BR Disney MD Small molecule chemical probes of microRNA function Curr Opin Chem Biol 2015 24 97 103 25500006 PMC4382669 source

  • May combine two claims.

    Premisecitation

    Many miRNAs have a strong tissue-specific expression pattern and the 3' UTR of target gene plays a critical role in determining miRNA-target interaction.

    “Many miRNAs have a strong tissue-specific expression pattern and 3’ UTR of target gene plays a critical role in determining the miRNA-target interaction [136, 137].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [136] Ludwig N Leidinger P Becker K Backes C Fehlmann T Pallasch C Rheinheimer S Meder B Stahler C Meese E Keller A Distribution of miRNA expression across human tissues Nucleic Acids Res 2016 PMC4856985 26921406 source

      The Results section ('Frequency of miRNAs per tissue and tissue specificity of miRNAs'; page unavailable) reports 222 miRNAs with highly tissue-specific expression, supporting the first part of the sentence. Our copy does not address whether a target gene’s 3′ UTR determines miRNA–target interactions, so it does not support that part. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [137] Hoffman Y Bublik DR A PU Elkon R Biniashvili T Agami R Oren M Pilpel Y 3'UTR Shortening Potentiates MicroRNA-Based Repression of Pro-differentiation Genes in Proliferating Human Cells PLoS Genet 2016 12 e1005879 26908102 PMC4764332 source

      The Introduction (page not provided) says that the position of a binding site along a target’s 3′ UTR can influence whether miRNA repression occurs, supporting the 3′ UTR part of the claim. The passages on miRNA expression concern changes between cellular states, not a strong tissue-specific expression pattern for many miRNAs; searches for tissue-specific miRNA expression did not establish that part. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    APOE4 allele increases the risk of developing AD, whereas APOE2 allele is protective.

    “APOE4 allele increases the risk of developing AD, whereas APOE2 allele is protective [70, 71].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [70] Corder EH Saunders AM Strittmatter WJ Schmechel DE Gaskell PC Small GW Roses AD Haines JL Pericak-Vance MA Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families Science 1993 261 921 923 8346443 source
    • cites [71] Corder EH Saunders AM Risch NJ Strittmatter WJ Schmechel DE Gaskell PC Jr. Rimmler JB Locke PA Conneally PM Schmader KE Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease Nat Genet 1994 7 180 184 7920638 source
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  • The paper relies on this without support.

    Delivering small molecules across the blood-brain barrier is one of the major obstacles in clinical application for brain diseases.

    “Delivering small molecules across BBB is one of the major obstacles in clinical application for brain diseases.”
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Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1016/j.expneurol.2006.03.019

    Major

    The cited work was retracted on 2006-08-01 (notice 10.1016/j.expneurol.2006.03.019), before this paper was published (2016-12). Its authors could have known.

    Cited work 10.1016/j.expneurol.2006.03.019 · retracted 2006-08-01 · notice 10.1016/j.expneurol.2006.03.019 · this paper published 2016-12

  • Cites a retracted work: 10.1074/jbc.m300466200

    Info

    The cited work was retracted on 2022-05-26 (notice 10.1016/j.jbc.2022.102052), not before this paper was published (2016-12).

    Cited work 10.1074/jbc.m300466200 · retracted 2022-05-26 · notice 10.1016/j.jbc.2022.102052 · this paper published 2016-12

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2 retracted

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1 of the 150 references couldn’t be matched to a known paper.

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Authors
Yoon, H., Flores, L. F., & Kim, J.
Affiliations
Mayo Clinic (US)
Corresponding author
Kim, Jungsu
ORCID
Venue
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Publisher
Elsevier BV
Published
2016-12
Volume
1861
Issue
12
Pages
2139-2147
ISSN
1388-1981 (ISSN-L)
DOI
10.1016/j.bbalip.2016.04.020
PMC
PMC5097035
OpenAlex
W2347000244
Semantic Scholar
e14b5e4d21041796fd59a8c598ee21fd2f38c68a
Cited by
23
References
150
Citations by year
2025: 3 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 1 · 2018: 3 · 2017: 3 · 2016: 3
FWCI
3.32
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • Mayo Graduate School
  • GHR Foundation
  • NIH (P50 AG016574)
Topics
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
microRNA, brain cholesterol metabolism, cholesterol homeostasis, Alzheimer's disease, neurodegenerative diseases, post-transcriptional regulation, lipid metabolism, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Brain, Cholesterol, Humans, MicroRNAs, Lipid Metabolism

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 ›

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