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Cited by 42Alzheimer's disease research and treatmentsCholesterol and Lipid MetabolismNeuroinflammation and Neurodegeneration Mechanisms

The DOI matches its Crossref record; 67 of the 67 references it cites were found in a registry or an index; 9 of the 33 sources its claims cite were checked for support.

LDLR Expression and Localization Are Altered in Mouse and Human Cell Culture Models of Alzheimer's Disease

Open access
Abisambra, Jose F., Fiorelli, Tina, Padmanabhan, Jaya, Neame, Peter, Wefes, Inge, Potter, Huntington·2010·PLoS ONE
DOI 10.1371/journal.pone.0008556PMC PMC2797391
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Abstract

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common form of dementia. The major molecular risk factor for late-onset AD is expression of the epsilon-4 allele of apolipoprotein E (apoE), the major cholesterol transporter in the brain. The low-density lipoprotein receptor (LDLR) has the highest affinity for apoE and plays an important role in brain cholesterol metabolism. METHODOLOGY/PRINCIPAL FINDINGS: Using RT-PCR and western blotting techniques we found that over-expression of APP caused increases in both LDLR mRNA and protein levels in APP transfected H4 neuroglioma cells compared to H4 controls. Furthermore, immunohistochemical experiments showed aberrant localization of LDLR in H4-APP neuroglioma cells, Abeta-treated primary neurons, and in the PSAPP transgenic mouse model of AD. Finally, immunofluorescent staining of LDLR and of gamma- and alpha-tubulin showed a change in LDLR localization preferentially away from the plasma membrane that was paralleled by and likely the result of a disruption of the microtubule-organizing center and associated microtubule network. CONCLUSIONS/SIGNIFICANCE: These data suggest that increased APP expression and Abeta exposure alters microtubule function, leading to reduced transport of LDLR to the plasma membrane. Consequent deleterious effects on apoE uptake and function will have implications for AD pathogenesis and/or progression.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In H4 neuroglioma cells overexpressing APP and in Aβ-treated primary neurons, LDLR mRNA/protein increase but LDLR is mislocalized away from the plasma membrane and accumulates perinuclear/TGN. PSAPP mice show increased LDLR and APP−/− mice decreased LDLR, suggesting APP/Aβ alters microtubule/MTOC-dependent LDLR trafficking.

Key findings

  • H4-APP cells expressed about 12 times more APP than controls and had a 3-fold increase in LDLR mRNA (p=0.04) and a 4-fold increase in LDLR protein (p=0.01) versus H4 controls.
  • LDLR accumulated in a dense perinuclear region in 59% of H4-APP cells versus 10% of H4 cells (p=0.001), while LRP distribution was unchanged (72% vs 66%, p=0.56); cell-surface LDLR was reduced by 32% in H4-APP cells (p=0.03).
  • Aβ40- and Aβ42-treated primary neurons had 23% (p<0.05) and 13% (p<0.01) less surface LDLR than Aβ42 scrambled peptide-treated cells; Aβ40-treated cells also had 10% less surface LDLR than Aβ42-treated cells (p<0.05).
  • PSAPP mice had a 20% increase in brain LDLR (p=0.05) and a 30% increase in hippocampal LDLR (p=0.04), whereas APP−/− mice had a 55% decrease in LDLR (p=0.04); α-tubulin was diffuse in 82% of H4-APP cells versus 87% of H4 cells (p=0.04), and γ-tubulin diffuse signal was 0.64% versus 0.72% (p=0.01).

Methods

  • H4 human neuroglioma cells stably transfected with human wild-type APP (H4-APP) were compared with non-transfected H4 controls; primary cortical neurons from E18 NTG mice were treated with 1 µM Aβ40, Aβ42, or scrambled Aβ42 for 48 hours; PSAPP, APP−/−, and age-matched NTG mice were analyzed at 10 months.
  • RT-PCR, western blotting, immunofluorescence/immunohistochemistry with LDLR, LRP, organelle markers (GM130, LAMP1, EEA1, KDEL), and α-/γ-tubulin were used, with ImageJ quantification and paired t-tests; independent experiments were repeated at least three times.

Limitations

  • The paper states no explicit limitations section; it notes that whether LDLR is involved in AD pathogenesis/progression “remains unanswered” and that prior LDLR/AD mouse studies have produced conflicting results.
  • Evident from the text: the findings are largely correlational, with no direct assay of apoE/cholesterol uptake or LDLR function and no microtubule rescue/manipulation to establish causality.
  • Evident from the text: some effects are modest and sample sizes are small (e.g., western blots n=3–5; tubulin differences of 0.08% and 5%), and the H4-APP overexpression model may not reflect physiological APP levels.

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

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0008556

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

9 of 33 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Aβ production and amyloid production reduce cell surface levels of other proteins including the NMDA receptor and the EphB2 receptor, both involved in synaptic plasticity.

    “Indeed Aβ production and amyloid production has been shown to reduce cell surface levels of other proteins including the NMDA receptor and the EphB2 receptor, both involved in synaptic plasticity [57], [58].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [57] EM Snyder, 2005, Regulation of NMDA receptor trafficking by amyloid-beta., Nat Neurosci source
    • cites [58] PN Lacor, 2007, Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease., J Neurosci source

      The section “Plasticity-linked receptors show decreased levels after ADDL exposure” and Figure 3 report reduced cell-surface NMDA receptors and EphB2 after exposure to Aβ oligomers; the Discussion links both receptors to synaptic plasticity. The experiments tested oligomer exposure, not whether Aβ or amyloid production itself reduced receptor levels. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Findingown data

    The PSAPP mouse model of AD shows a mild, yet significant increase in LDLR protein.

    “Concomitantly, the PSAPP mouse model of AD, which over-expresses the full-length human APP containing the V717F mutation, also shows aberrant distribution and a mild, yet significant increase in LDLR protein.”
    Quote in the paperSubstantial claim
  • Findingown data

    LDLR protein is increased 4-fold in H4-APP cells compared to H4 controls.

    “Quantification of the immunoblots showed a 4-fold increase in LDLR protein in H4-APP cells compared to H4 controls (Figure 1C).”
    Quote in the paperSubstantial claim
  • Findingown data

    APP−/− mice at 10 months have a 55% decrease in brain LDLR compared to age-matched controls.

    “Interestingly, we found that LDLR was decreased by 55% in these mice compared to age-matched controls (Figure 6C and 6D; *p = 0.04).”
    Quote in the paperSubstantial claim
  • Findingown data

    Aβ40-treated cortical neurons had 23% less surface LDLR compared to Aβ42 scrambled peptide-treated cells.

    “the Aβ40- and Aβ42-treated cortical neurons had 23% (*p<0.05) and 13% (**p<0.01) less surface LDLR compared to Aβ42 scrambled peptide-treated cells (Figure 3C).”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim. 17
  • It may state two separate claims as one. 22

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The ε-4 isoform of apoE is the strongest molecular risk factor for the development of AD.

    “The ε-4 isoform of apoE is the strongest molecular risk factor for the development of AD. About 60–80% of AD patients have at least one copy of apoE4 [2], [4], [5] and the risk for AD is increased in an ε-4 allele dose-dependent manner [6].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [2] WJ Strittmatter, 1993, Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease., Proc Natl Acad Sci U S A source

      The Materials and Methods passage (page not provided) reports that APOE-ε4 was significantly more frequent in patients from families with Alzheimer disease than in controls. The paper focuses on late-onset familial Alzheimer disease and suggests, rather than establishes, a functional role for apoE4; it does not establish that apoE4 is the strongest molecular risk factor for AD generally. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [4] RW Mahley, 2006, Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease., Proc Natl Acad Sci U S A source

      The 'ApoE and Neuropathology' section calls apoE4 the major known genetic risk factor for AD in many populations. That supports its importance as a risk factor, but does not establish that it is the strongest molecular risk factor across all populations. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [5] AM Saunders, 1993, Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease., Neurology source

      The passage indexed under Statistical analysis (page not supplied) describes APOE ε4 as a possible susceptibility gene or risk factor for late-onset AD. It does not rank ε4 as the strongest molecular risk factor, and its findings do not establish that claim for AD generally. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Several groups identified a potential contribution of LDLR to AD and investigated potential links, with some apparently opposing results.

    “Several groups identified a potential contribution of LDLR to AD and investigated potential links, for example by crossing AD transgenic mice with the LDLR−/− mouse model of hypercholesterolemia to investigate the effects of LDLR deficiency [30]–[40]. Some apparently opposing results were obtained.”
    Quote in the paperNot a substantial claim2 of 10 sources checked
    • cites [30] R Scacchi, 2001, Polymorphisms of the apolipoprotein E gene regulatory region and of the LDL receptor gene in late-onset Alzheimer's disease in relation to the plasma lipidic pattern., Dement Geriatr Cogn Disord source
    • cites [31] A Papassotiropoulos, 2005, A cluster of cholesterol-related genes confers susceptibility for Alzheimer's disease., J Clin Psychiatry source
    • cites [32] R Lamsa, 2008, Genetic study evaluating LDLR polymorphisms and Alzheimer's disease., Neurobiol Aging source
    • cites [33] D Cheng, 2005, Functional interaction between APOE4 and LDL receptor isoforms in Alzheimer's disease., J Med Genet source

      The Discussion reports an earlier study finding no association between two LDLR polymorphisms and late-onset AD, while the paper's own results associate an LDLR genotype combination with increased AD risk in APOE4 carriers. This supports investigation of a potential LDLR–AD link and apparently differing findings. The cited paper studies human genotypes, however; it does not report crossing AD transgenic mice with LDLR-deficient mice, the example included in the cited sentence. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [34] D Blacker, 2003, Results of a high-resolution genome screen of 437 Alzheimer's disease families., Hum Mol Genet source
    • cites [35] EM Wijsman, 2004, Evidence for a novel late-onset Alzheimer disease locus on chromosome 19p13.2., Am J Hum Genet source

      The Discussion identifies LDLR as near a chromosome 19p linkage signal and calls its possible connection to Alzheimer disease suggestive. It does not report crossing AD transgenic mice with LDLR-deficient mice or opposing results from such experiments; the mouse evidence mentioned elsewhere concerns LRP, a different receptor. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [36] EH Corder, 2006, Membership in genetic groups predicts Alzheimer disease., Rejuvenation Res source
    • cites [37] RK Gopalraj, 2005, Genetic association of low density lipoprotein receptor and Alzheimer's disease., Neurobiol Aging source
    • cites [38] H Li, 2008, Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease., Arch Neurol source
    • cites [39] W Retz, 2001, Potential genetic markers of sporadic Alzheimer's dementia., Psychiatr Genet source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    The serum cholesterol and lipid profiles of individuals with trisomy 21 are abnormal, yet they are protected against atherosclerosis.

    “Interestingly, the serum cholesterol and lipid profiles of these individuals are abnormal, yet they are protected against atherosclerosis [55], [56].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [55] JC Murdoch, 1977, Down's syndrome: an atheroma-free model?, Br Med J source

      The Abstract reports no atheroma in five patients with Down’s syndrome and significantly lower triglycerides than in people living at home. It also says cholesterol and triglyceride concentrations were similar to those of the institutional control group. The claim overstates the evidence by describing cholesterol profiles generally as abnormal and protection against atherosclerosis as established for all individuals with trisomy 21. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [56] S Yla-Herttuala, 1989, Down's syndrome and atherosclerosis., Atherosclerosis source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    In the CNS, apoE-cholesterol is principally made in astrocytes and exported to neurons; neurons can also produce apoE-cholesterol during stress.

    “In the CNS, apoE-cholesterol is principally made in astrocytes and exported to neurons [9], [10]; however, neurons can also produce apoE-cholesterol during stress [11].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [9] JK Boyles, 1985, Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system., J Clin Invest source

      The Discussion reports that astrocytes secrete apoE, supporting the astrocytic-source portion attributed to this paper. It describes lipid redistribution among nervous-system cells as a possibility, not a demonstrated export of apoE-cholesterol to neurons, and does not establish where the cholesterol is made. The separate claim about neurons under stress is attached to [11], not this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [10] NA Elshourbagy, 1985, Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other peripheral tissues of rats and marmosets., Proc Natl Acad Sci U S A source

      The Discussion says astrocytes appear to be the major, if not the only, brain cells containing apoE. It describes cholesterol transport as a possible role for brain apoE, but does not establish that astrocytes export apoE-associated cholesterol to neurons. The separate claim about neuronal production during stress is attached to citation [11], not this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [11] Q Xu, 2006, Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus., J Neurosci source

  • It may state two separate claims as one.

    Findingown data

    The percentage of diffuse γ-tubulin signal was 0.64% in H4-APP cells and 0.72% in H4 cells, a difference of 0.08% that was statistically significant (p=0.01).

    “where 0.64% of the γ-tubulin signal was dispersed in H4-APP cell. In contrast, 0.72% percent of the γ-tubulin signal was diffuse in the H4 cells; this was a modest change (0.08%), yet it was significantly different (*p = 0.01; Figure 8C).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Only 82% of α-tubulin signal in H4-APP cells was diffuse, while H4 cells had 87% of total α-tubulin signal spread throughout the cell.

    “We found that only 82% of the alpha-tubulin signal in H4-APP cells was diffuse, while H4 cells had 87% of the total α-tubulin signal spread throughout the cell (Figure 9A and 9B).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    In PSAPP mice, LDLR signal is increased in the hippocampus, with the strongest effect in the CA3 region.

    “We detected an increase in the LDLR signal in the hippocampus of PSAPP mice, a region that is particularly affected by the amyloid pathology. This effect was the strongest in the CA3 region of the hippocampus (Figure 7A).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In H4-APP cells, LDLR mRNA and protein levels are increased.

    “In H4-APP cells, a human neuroglioma cell line stably over-expressing human wild-type APP, LDLR mRNA and protein levels are increased.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    H4-APP cells express about 12 times more APP than non-transfected controls and APP is distributed throughout the whole cell.

    “H4-APP cells express about 12 times more APP than non-transfected controls and it is distributed throughout the whole cell (Figure S1).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    H4-APP cells show a diffuse, non-nuclear pattern of γ-tubulin signal, whereas H4 cells show condensed γ-tubulin staining.

    “While we observed condensed staining of γ-tubulin in H4 cells, H4-APP cells showed a diffuse, non-nuclear pattern of γ-tubulin signal (Figure 8A and 8B)”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In H4-APP cells, LDLR is densely concentrated in the perinuclear region, whereas in H4 control cells LDLR is homogeneously distributed.

    “At closer inspection (Figure 2B), we confirmed that in H4 control cells, LDLR is homogeneously distributed, whereas in H4-APP cells, LDLR appears to converge to form a dense perinuclear core.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Cells surrounding the neuronal layer of the hippocampus in PSAPP tissues show dense accumulation of LDLR similar to H4-APP cells, whereas NTG counterparts lack that signal concentration.

    “At higher magnification, we found that cells surrounding the neuronal layer of the hippocampus in PSAPP tissues also showed a dense accumulation of LDLR similar to that observed in H4-APP cells (arrowhead in PSAPP hippocampal cell of figure 7A), whereas the NTG counterpart lacked that same signal concentration (Figure 7A).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In H4-APP cells, LDLR signal co-localized in the Golgi apparatus and lysosomes, or the trans-Golgi network.

    “We found that in H4-APP cells, LDLR signal co-localized in the Golgi apparatus and lysosomes, or the trans-Golgi network.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Increased APP expression and Aβ exposure alters microtubule function, leading to reduced transport of LDLR to the plasma membrane.

    “These data suggest that increased APP expression and Aβ exposure alters microtubule function, leading to reduced transport of LDLR to the plasma membrane.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductnone given

    All data reported were obtained from independent experiments repeated at least three times.

    “All data reported were obtained from independent experiments repeated at least three times.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Images of H4 and H4-APP cells without primary antibody incubation were used as a negative control of the assay.

    “Images of H4 and H4-APP cells without primary antibody incubation are shown as a negative control of the assay (Figure 2A).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    RT-PCR and western blot experiments were conducted in triplicate.

    “RT-PCR and western blot experiments were conducted in triplicate.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    The centrosome's nucleation function for microtubule formation may be disrupted by association with excess levels of APP or Aβ in the over-expression models or by mutations of the APP gene.

    “As a result, the centrosome's nucleation function for microtubule formation may be disrupted by association with excess levels of APP or Aβ in our over-expression models or by mutations of the APP gene.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    The translation of LDLR mRNA yields a 120 kDa protein that is post-translationally modified in the Golgi apparatus into the mature, 160 kDa LDLR.

    “The translation of LDLR mRNA yields a 120 kDa protein that is post-translationally modified in the Golgi apparatus into the mature, 160 kDa LDLR [20], [21].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] H Tolleshaug, 1982, Posttranslational processing of the LDL receptor and its genetic disruption in familial hypercholesterolemia., Cell source
    • cites [21] T Yamamoto, 1984, The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA., Cell source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Over 18,000 cell nuclei were taken into account from three independent experiments.

    “Over 18,000 cell nuclei were taken into account from three independent experiments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    APP and PS1 bind to the centrosome.

    “It was previously reported that PS1 and APP bind to the centrosome [41], [42].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [41] M Nizzari, 2007, Amyloid precursor protein and Presenilin 1 interaction studied by FRET in human H4 cells., Ann N Y Acad Sci source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [42] J Li, 1997, Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation., Cell source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Liver whole cell lysates from NTG and LDLR−/− mice were used as positive and negative control homogenates.

    “liver whole cell lysates were prepared from NTG and LDLR−/− as positive and negative control homogenates, respectively.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Net cholesterol import into the cell could be decreased, leading to upregulation of LDLR transcription and protein levels.

    “Consequently, net cholesterol import into the cell could be decreased, leading to upregulation of LDLR transcription and protein levels.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: In order for apoE-cholesterol to enter the cell, LDLR must be localized to the plasma membrane.

  • Probably not a substantial claim.

    Study design and conductnone given

    Experiments were done in triplicate using brain sections of 8 mice for each condition.

    “Experiments were done in triplicate using brain sections of 8 mice for each condition.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    LDLR is a membrane-spanning glycoprotein that plays a critical role in removing LDL and VLDL from the blood.

    “LDLR is a membrane-spanning glycoprotein that plays a critical role in removing LDL and VLDL from the blood [16], [17].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] JL Goldstein, 1976, The LDL pathway in human fibroblasts: a receptor-mediated mechanism for the regulation of cholesterol metabolism., Curr Top Cell Regul source
    • cites [17] TC Sudhof, 1985, The LDL receptor gene: a mosaic of exons shared with different proteins., Science source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Interpretationown data

    Trafficking of other proteins, organelles, or vesicles in the cell may also be disturbed, although this cannot be true for all proteins as LRP localization was unchanged in H4-APP cells.

    “Our results provide evidence that trafficking of other proteins, organelles, or vesicles in the cell may also be disturbed, although this cannot be true for all proteins as LRP localization was unchanged in the H4-APP cells. (Figure 2A).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Under low intracellular sterol levels, LDLR gene expression is primarily and directly activated by SREBPs and secondarily by thyroid hormone.

    “Under low intracellular sterol levels, LDLR gene expression is primarily and directly activated by sterol response element-binding proteins (SREBPs) [18] and secondarily by thyroid hormone [19].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] JR Smith, 1990, Identification of nucleotides responsible for enhancer activity of sterol regulatory element in low density lipoprotein receptor gene., J Biol Chem source
    • cites [19] D Lopez, 2007, Activation of the hepatic LDL receptor promoter by thyroid hormone., Biochim Biophys Acta source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Upon maturation, LDLR is transported to the cell membrane via a clathrin-coated pit vesicle.

    “Upon maturation, LDLR is transported to the cell membrane via a clathrin-coated pit vesicle [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] CG Davis, 1987, The low density lipoprotein receptor. Identification of amino acids in cytoplasmic domain required for rapid endocytosis., J Biol Chem source

  • It may state two separate claims as one.

    Interpretationown data

    Aberrant localization of LDLR occurs in H4-APP neuroglioma cells, Aβ-treated primary neurons, and in the PSAPP transgenic mouse model of AD.

    “immunohistochemical experiments showed aberrant localization of LDLR in H4-APP neuroglioma cells, Aβ-treated primary neurons, and in the PSAPP transgenic mouse model of AD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationnone given

    The H4-APP cells and PSAPP mouse models evaluated emulate the APP-induced amyloidogenic effects seen in individuals with trisomy 21.

    “The H4-APP cells and PSAPP mouse models we evaluated emulate the APP-induced amyloidogenic effects seen in individuals with trisomy 21.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    A total of ∼18,000 cells were taken into account from three independent experiments.

    “A total of ∼18,000 cells were taken into account from three independent experiments.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    The change in LDLR localization preferentially away from the plasma membrane is paralleled by and likely the result of a disruption of the microtubule-organizing center and associated microtubule network.

    “immunofluorescent staining of LDLR and of γ- and α-tubulin showed a change in LDLR localization preferentially away from the plasma membrane that was paralleled by and likely the result of a disruption of the microtubule-organizing center and associated microtubule network.”
    Quote in the paperSubstantial claim
32 of 32

  • The paper relies on this without support.

    In order for apoE-cholesterol to enter the cell, LDLR must be localized to the plasma membrane.

    “In order for apoE-cholesterol to enter the cell, LDLR must be localized to the plasma membrane.”

  • The paper relies on this without support.

    The H4-APP cell model and PSAPP mouse model are physiologically relevant to human AD.

    “We next sought to reproduce the APP-induced LDLR over-expression and mis-localization in a physiologically relevant experimental system—an in vivo model of AD.”

  • The paper relies on this without support.

    Aβ treatment of primary neurons models AD-relevant Aβ exposure.

    “In order to assess the general relevance of the redistribution of the LDLR in H4-APP cells, we repeated the experiment using cultured mouse cortical neurons from normal mice and exposing them to 1uM of either Aβ40 or Aβ42 for 48 hours”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • γ-tubulin measurements reverse the reported direction

    Major

    The text and Figure 8 caption say γ-tubulin is more widely distributed in H4-APP cells, but the stated diffuse-signal values are lower in H4-APP cells (0.64%) than in H4 controls (0.72%).

  • Figure 5 organelle panel labels are reversed

    Minor

    The Results assign panels E-F to the endoplasmic reticulum and G-H to early endosomes; the Figure 5 caption assigns those panels to the opposite organelles.

  • Neuronal LDLR result cites the H4-cell panel

    Minor

    The neuronal Aβ-treatment result points to Figure 3C, but the Figure 3 caption identifies that panel as quantification of H4 and H4-APP cells, not neurons.

3 of 3

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Metadata

Authors
Abisambra, J. F., Fiorelli, T., Padmanabhan, J., Neame, P., Wefes, I., & Potter, H.
Affiliations
University of South Florida (US)
Corresponding author
Potter, Huntington
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2010-01-01
Volume
5
Issue
1
Pages
e8556
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0008556
PMC
PMC2797391
OpenAlex
W2115245514
Cited by
42
References
67
Citations by year
2025: 2 · 2024: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 3 · 2017: 1 · 2016: 3 · 2015: 3 · 2014: 4 · 2013: 5 · 2012: 5
FWCI
1.76
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, LDL receptor, apolipoprotein E, amyloid-beta, APP overexpression, brain cholesterol metabolism, microtubule organizing center, microtubule cytoskeleton, plasma membrane localization
MeSH terms
Alzheimer Disease, Animals, Brain, Cells, Cultured, Disease Models, Animal, Humans, Immunohistochemistry, Receptors, LDL, RNA, Messenger, Tubulin, Blotting, Western, Reverse Transcriptase Polymerase Chain Reaction, Mice

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.

A language model drew the claims from the paper on 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (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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