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Cited by 91Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsBarrier Structure and Function Studies

The DOI matches its Crossref record; 61 of the 62 references it cites were found in a registry or an index; 9 of the 65 sources its claims cite were checked for support.

Increased Extracellular Amyloid Deposition and Neurodegeneration in Human Amyloid Precursor Protein Transgenic Mice Deficient in Receptor-Associated Protein

Open access
Van Uden, Emily, Mallory, Margaret, Veinbergs, Isaac, Alford, Michael, Rockenstein, Edward, Masliah, Eliezer·2002·The Journal of Neuroscience
DOI 10.1523/jneurosci.22-21-09298.2002PMC PMC6758061
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Abstract

The low-density lipoprotein receptor-related protein (LRP) is an abundant neuronal cell surface receptor that regulates amyloid beta-protein (Abeta) trafficking into the cell. Specifically, LRP binds secreted Abeta complexes and mediates its degradation. Previously, we have shown in vitro that the uptake of Abeta mediated by LRP is protective and that blocking this receptor significantly enhances neurotoxicity. To further characterize the effects of LRP and other lipoprotein receptors on Abeta deposition, an in vivo model of decreased LRP expression, receptor-associated protein (RAP)-deficient (RAP-/-) mice was crossed with human amyloid protein precursor transgenic (hAPP tg) mice, and plaque formation and neurodegeneration were analyzed. We found that, although the age of onset for plaque formation was the same in hAPP tg and hAPP tg/RAP-/- mice, the amount of amyloid deposited doubled in the hAPP tg/RAP-/- background. Moreover, these mice displayed increased neuronal damage and astrogliosis. Together, these results further support the contention that LRP and other lipoprotein receptors might be neuroprotective against Abeta toxicity and that this receptor might play an integral role in Abeta clearance.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

Crossing human amyloid precursor protein transgenic (hAPP tg) mice with receptor-associated protein-deficient (RAP−/−) mice, which have reduced LRP and other lipoprotein receptors, increased extracellular amyloid deposition and neurodegeneration without changing plaque onset age. The authors conclude that LRP and related lipoprotein receptors likely protect against Aβ toxicity by promoting Aβ clearance.

Key findings

  • Plaque onset was similar in hAPP tg and hAPP tg/RAP−/− mice at ~10 months, but hAPP tg/RAP−/− mice had higher plaque load at both 10 and 18 months; the abstract states the amount of amyloid deposited doubled in the hAPP tg/RAP−/− background.
  • Hippocampal Aβ1-42 levels were elevated in hAPP tg/RAP−/− mice, whereas hAPP mRNA/protein expression was comparable between hAPP tg groups; LRP immunoreactivity was reduced by ~80% and LDL-R by ~40% in RAP−/− groups.
  • hAPP tg/RAP−/− mice showed increased astrogliosis and additional decreases in MAP2-immunoreactive dendrites compared with hAPP tg mice, while RAP−/− mice alone had normal MAP2 levels.
  • No amyloid deposits were detected in non-tg controls or RAP−/− mice.

Methods

  • hAPP tg mice expressing mutant human APP (line J9; PDGF promoter; V717F and K670M/N671L mutations) were crossed with RAP−/− mice; groups included non-tg RAP+/+ (n = 15 at 10 months, n = 14 at 18 months), non-tg RAP−/− (n = 8, n = 8), hAPP tg (n = 15, n = 14), and hAPP tg/RAP−/− (n = 5, n = 5).
  • Brains were analyzed by RNase protection assay, Western blot, immunohistochemistry for Aβ (3D6, R1280), GFAP, and MAP2, and ELISA for Aβ1-40 and Aβ1-42; plaque load and GFAP/MAP2 immunoreactivity were quantified with image analysis.
  • Statistical comparisons used one-way ANOVA with Dunnett’s or Tukey–Kramer post hoc tests, simple regression, and a 0.05 significance level; mice were coded for blinded assessment.

Limitations

  • Stated: RAP also regulates other lipoprotein receptors such as LDL-R, VLDL-R, and apoER2, so the authors cannot completely rule out contributions from decreased expression of other receptors; future crosses with VLDL-R−/−, apoER2−/−, or LDL-R−/− mice were said to be necessary.
  • Stated: the precise mechanisms by which LRP regulates Aβ levels remain complex and controversial, with conflicting in vitro findings on whether LRP activity increases or decreases Aβ production.
  • Evident from the text: the hAPP tg/RAP−/− group was small (n = 5 per age), and the model uses RAP deletion rather than an LRP-specific knockout because homozygous LRP knockout is lethal, limiting direct attribution to LRP alone.

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

Integrity signals

Registry

Crossref · 10.1523/jneurosci.22-21-09298.2002

Cites

61 of 61 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

9 of 65 cited sources checked · 5 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    FRET experiments have shown close opposition of extracellular domains of KPI-containing APP and LRP that is RAP sensitive.

    “because fluorescence resonance energy transfer experiments have shown that there is a close opposition of the extracellular domains of KPI-containing APP and LRP that is RAP sensitive (Kinoshita et al., 2001).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Kinoshita et al., 2001 source
  • Interpretationcitation

    LRP might regulate Aβ clearance.

    “and supports the possibility that LRP might regulate A␤ clearance (Kang et al., 2000).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Kang et al., 2000 source
  • Premisecitation

    Aβ binding to other LRP ligands, such as apoE, also contributes to reduced Aβ levels.

    “Furthermore, A␤ binding to other LRP ligands, such as apoE, also contributes to reduced A␤ levels (Kang et al., 2000;Shibata et al., 2000;Herz and Strickland, 2001).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Kang et al., 2000 source
    • cites Shibata et al., 2000 source
    • cites Herz and Strickland, 2001 source
  • Findingown data

    The age of onset for plaque formation was the same in hAPP tg and hAPP tg/RAP-/- mice.

    “although the age of onset for plaque formation was the same in hAPP tg and hAPP tg/RAPϪ/Ϫ mice”
    Quote in the paperNot a substantial claim
  • Findingown data

    The amount of amyloid deposited doubled in the hAPP tg/RAP-/- background compared to hAPP tg.

    “the amount of amyloid deposited doubled in the hAPP tg/RAPϪ/Ϫ background”
    Quote in the paperSubstantial claim
  • It may state two separate claims as one. 26
  • Probably not a substantial claim. 33

  • It may state two separate claims as one.

    Premisecitation

    LRP and other lipoprotein receptors might play a role in AD by influencing the clearance of Aβ and the processing of APP.

    “Moreover, LRP and other lipopro-tein receptors might play a role in AD by influencing the clearance of amyloid ␤-protein (A␤) and the processing of APP”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Trommsdorff et al., 1998 source

      The discussion (page unavailable in our copy) proposes that LRP may affect APP trafficking and the rate of its amyloidogenic processing, supporting a possible role in Alzheimer’s disease through APP processing. Our copy does not say that LRP or other lipoprotein receptors influence Aβ clearance. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Ulery et al., 2000 source

      The paper’s Discussion and APP-processing results report that LRP influences APP processing and Aβ production, supporting a possible role for LRP in Alzheimer’s disease. The passages do not establish an effect on Aβ clearance or show that other lipoprotein receptors have the same role; uptake of APP and other ligands is not evidence of Aβ clearance. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Rebeck et al., 2001 source

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

    Premisecitation

    A polymorphism in exon 3 of the LRP gene (C776T) has been associated with increased risk for late onset AD.

    “and a polymorphism in exon 3 of the LRP gene (C776T) has been associated with increased risk for late onset AD (Kang et al., 1997(Kang et al., , 2000)).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Kang et al., 1997 source
    • cites Kang et al., 2000 source

      The Introduction reports an association between an exon 3 LRP polymorphism and late-onset Alzheimer’s disease, but identifies it as C766T, not C776T. The Discussion describes the T allele as protective rather than associated with increased risk; the claim does not specify which allele carries the increased risk. (LLM, conf=0.88)

      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

    RAGE, SR-A, and FPRL1 are primarily found in macrophages, and Aβ binds to them as a free peptide.

    “In contrast, RAGE, SR-A, and FPRL1 are primarily found in macrophages, and A␤ binds to them as a free peptide (Shibata et al., 2000;Yazawa et al., 2001).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Shibata et al., 2000 source

      The Introduction (p. 2) says RAGE and SR-A bind Aβ as a free peptide. It does not mention FPRL1 or say that these receptors are primarily found in macrophages; instead, it discusses RAGE and SR-A in brain endothelial transport. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Yazawa et al., 2001 source

  • It may state two separate claims as one.

    Premisecitation

    Long-term treatment with RAP results in increased levels of both cell surface APP and secreted APP α, along with decreased Aβ production.

    “Long-term treatment with RAP results in increased levels of both cell surface APP and secreted APP ␣, along with decreased A␤ production (Ulery et al., 2000).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Ulery et al., 2000 source

  • It may state two separate claims as one.

    Findingown data

    hAPP tg/RAP-/- mice displayed increased neuronal damage and astrogliosis.

    “Moreover, these mice displayed increased neuronal damage and astrogliosis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Findingown data

    Patterns of dendritic degeneration in hAPP tg/RAP−/−.

    “Patterns of dendritic degeneration in hAPP tg/RAPϪ/Ϫ.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Mild astrogliosis in non-tg mice.

    “M, Mild astrogliosis in non-tg mice.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    hAPP tg and hAPP tg/RAP-/- mice developed typical AD-like plaques at ~10 months of age, with progressive accumulation of plaques observed at 18 months of age.

    “In contrast, hAPP tg (Fig. 3 B, I,J ) and hAPP tg/RAPϪ/Ϫ mice (Fig. 3 D, H,L) developed typical AD-like plaques at ϳ10 months of age, with progressive accumulation of plaques observed at 18 months of age (Fig. 4 A).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Non-tg and hAPP tg mice showed extensive LRP immunostaining of pyramidal neurons in the neocortex.

    “Non-tg ( I ) and hAPP tg ( J) mice showed extensive LRP immunostaining of pyramidal neurons in the neocortex.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    No amyloid deposits were detected in non-tg controls and in RAP-/- mice.

    “No amyloid deposits were detected in non-tg controls (Fig. 3A) and in RAPϪ/Ϫ mice (Fig. 3C).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Mild astroglial immunostaining in RAP−/− mice.

    “O, Mild astroglial immunostaining in RAPϪ/Ϫ mice.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    hAPP tg mice showed extensive immunostaining of pyramidal neurons in the neocortex.

    “F, hAPP tg mice showed extensive immunostaining of pyramidal neurons in the neocortex.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Findingnone given

    In RAP−/− and hAPP tg/RAP−/− mice, LRP immunoreactivity was decreased.

    “In the RAPϪ/Ϫ ( G) and hAPP tg/RAPϪ/Ϫ ( H ), no LRP levels of LRP immunoreactivity were decreased.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisenone given

    LRP is an abundant neuronal cell surface receptor that regulates Aβ trafficking into the cell.

    “The low-density lipoprotein receptor-related protein (LRP) is an abundant neuronal cell surface receptor that regulates amyloid ␤-protein (A␤) trafficking into the cell.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Levels of LRP decrease with age.

    “Furthermore, levels of LRP decrease with age”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kang et al., 1997 source
    • cites Kang et al., 2000 source

  • It may state two separate claims as one.

    Premiseown data

    In vitro, uptake of Aβ mediated by LRP is protective and blocking this receptor significantly enhances neurotoxicity.

    “Previously, we have shown in vitro that the uptake of A␤ mediated by LRP is protective and that blocking this receptor significantly enhances neurotoxicity.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisenone given

    LRP binds secreted Aβ complexes and mediates its degradation.

    “Specifically, LRP binds secreted A␤ complexes and mediates its degradation.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    In the RAP-/- mice, LRP levels are reduced by 75-80%, whereas levels of LDL-R and VLDL-R are reduced by 40-50%.

    “However, it is worth noting that, in the RAPϪ/Ϫ mice, LRP levels are reduced by 75-80%, whereas levels of LDL-R and VLDL-R are reduced by 40 -50% (Veinbergs et al., 2001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Veinbergs et al., 2001 source

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

    Study design and conductnone given

    For all studies described, mice were coded to ensure objective assessment, and codes were not broken until the analysis was complete.

    “For all studies described, mice were coded to ensure objective assessment, and codes were not broken until the analysis was complete.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In the presence of α2M, LRP protects neural cell lines against the neurotoxic effects of Aβ.

    “In addition, previous studies have shown that, in the presence of ␣2M, LRP protects neural cell lines against the neurotoxic effects of A␤ (Fabrizi et al., 1999;Van Uden et al., 1999b, 2000).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Fabrizi et al., 1999 source
    • cites Van Uden et al., 1999b

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

    • cites Van Uden et al., 2000 source

  • Probably not a substantial claim.

    Premisecitation

    Binding of KPI-containing isoforms of APP (APP751 and APP770) to LRP results in increased Aβ production.

    “although binding of Kunitz protease inhibitor (KPI) containing isoforms of APP (APP751 and APP770) to LRP results in increased A␤ production”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Qiu et al., 1999 source
    • cites Rebeck et al., 2001 source

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

    Premisecitation

    RAP-/- mice are difficult to breed.

    “they are difficult to breed (Umans et al., 1999)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Umans et al., 1999 source

  • It may state two separate claims as one.

    Premisecitation

    Deletion of the RAP gene results in reduced trafficking of LRP and other lipoprotein receptors to the plasma membrane because this 39 kDa chaperone molecule facilitates the trafficking of lipoprotein receptors to the membrane.

    “Deletion of the R AP gene results in reduced trafficking of LRP and other lipoprotein receptors to the plasma membrane because this 39 kDa chaperone molecule (Bu, 2001) facilitates the trafficking of lipoprotein receptors to the membrane (Bu et al., 1995;Willnow et al., 1996).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bu, 2001

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

    • cites Bu et al., 1995

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

    • cites Willnow et al., 1996 source

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationreasoning

    Increasing LRP activity might represent a novel modality for treatment of AD.

    “and that increasing LRP activity might represent a novel modality for treatment of AD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Interpretationreasoning

    Reduced LRP levels may promote increased amyloid deposition in hAPP tg/RAP-/- mice by impeding the clearance of apoE, α2M, and lactoferrin.

    “Alternatively, reduced LRP levels may promote increased amyloid deposition in hAPP tg/RAPϪ/Ϫ mice by impeding the clearance of apoE, ␣2M, and lactoferrin”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    RAP−/− mice display deficient somatostatin release and memory deficits in the water maze that are ameliorated by apoE.

    “Furthermore, RAPϪ/Ϫ mice display deficient somatostatin release and memory deficits in the water maze (Van Uden et al., 1999a) that are ameliorated by another LRP ligand, namely apoE (Veinbergs et al., 2001).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Van Uden et al., 1999a

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

    • cites Veinbergs et al., 2001 source

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

    Premisecitation

    RAP blocked the enhancing effect of synaptic potentiation by exogenous application of tPA in hippocampal slices prepared from tPA knock-out mice, indicating that interactions between tPA and cell surface LRP are important for synaptic plasticity.

    “In addition, RAP also blocked the enhancing effect of synaptic potentiation by exogenous application of the LRP ligand tissue type plasminogen activator (tPA) in hippocampal slices prepared from tPA knock-out mice, indicating that interactions between tPA and cell surface LRP are important for synaptic plasticity (Zhuo et al., 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zhuo et al., 2000 source

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

    Premisecitation

    Other receptors involved in Aβ clearance include RAGE, SR-A, and FPRL1.

    “Other receptors involved in A␤ clearance include the receptor for advanced glycation end products (RAGE), scavenger receptor type A (SR-A) (Paresce et al., 1996;Yan et al., 1996;El Khoury et al., 1998), and the G-protein-coupled receptor formyl peptide receptor like-1 (FPRL1) (Yazawa et al., 2001).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Paresce et al., 1996 source
    • cites Yan et al., 1996 source
    • cites Yazawa et al., 2001 source

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

    Premisecitation

    The C-terminal site of APP interacts with LRP via the adapter protein Fe65.

    “Furthermore, the C-terminal site of APP interacts with LRP via the adapter protein Fe65”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Trommsdorff et al., 1998 source
    • cites Kinoshita et al., 2001 source

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

    Study design and conductnone given

    All sections in any given experiment were blind coded and processed in parallel to ensure objective assessments and reliability of results.

    “To ensure objective assessments and reliability of results, all sections in any given experiment were blind coded and processed in parallel.”
    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.

    Interpretationnone given

    Increased Aβ production could result from increased hAPP synthesis or cleavage by β and γ secretases.

    “Increased A␤ production could result from increased hAPP synthesis or cleavage by ␤ and ␥ secretases.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationcitation

    LRP might influence Aβ metabolism by different mechanisms, including direct interactions with APP, as well as internalization and clearance of Aβ bound to α2M.

    “Together, these studies suggest that LRP might influence A␤ metabolism by different mechanisms, including direct interactions with APP, as well as internalization and clearance of A␤ bound to ␣2M.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Premisecitation

    Decreased LRP levels are associated with decreased Aβ clearance.

    “recent studies in vitro and in AD brains suggests that decreased LRP levels are associated with decreased A␤ clearance (Kang et al., 2000)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kang et al., 2000 source

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

    Premisecitation

    LRP is found primarily in neurons, and Aβ binding is dependent on coupling to α2M, apoE, and apoJ.

    “For example, LRP is found primarily in neurons, and A␤ binding is dependent on coupling to ␣2M, apoE, and apoJ (Herz, 2001b).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Herz, 2001b

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

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

    Premisecitation

    APP-LRP interactions in CHO cells have shown that decreased LRP activity by genetic deletion or by addition of exogenous RAP could result in decreased Aβ production from hAPP770 transfected cells, and these ectodomain interactions alter the endocytic pathway.

    “APP-LRP interactions in CHO cells have shown that decreased LRP activity by genetic deletion or by addition of exogenous RAP could result in decreased A␤ production from hAPP770transfected cells, and these ectodomain interactions alter the endocytic pathway (Kinoshita et al., 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kinoshita et al., 2001 source

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

    Interpretationreasoning

    In the hAPP tg/RAP-/- mice, the effects of other RAP-dependent receptors on Aβ deposition might be less critical.

    “suggesting that, in the hAPP tg/RAPϪ/Ϫ mice, the effects of other RAP-dependent receptors on A␤ deposition might be less critical.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Aβ is one of the proteolytic products of APP metabolism generated from concerted cleavage at the N- and C-terminal site by β and γ secretase.

    “A␤ is one of the proteolytic products of APP metabolism generated from the concerted cleavage at the N-and C-terminal site of the molecule by ␤ and ␥ secretase, respectively”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Checler, 1995 source
    • cites Selkoe et al., 1996 source
    • cites Sinha et al., 2000 source

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

    Premisecitation

    RAP-/- mice do not exhibit any gross alterations.

    “although R APϪ/Ϫ mice do not exhibit any gross alterations (Willnow et al., 1995;Umans et al., 1999;Van Uden et al., 1999a)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Willnow et al., 1995 source
    • cites Umans et al., 1999 source
    • cites Van Uden et al., 1999a

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

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

    Premisecitation

    In human neuroglioma (H4) cells, lack of LRP activity results in decreased Aβ production, whereas the presence of functional LRP is associated with increased production and secretion of Aβ.

    “For example, in human neuroglioma (H4) cells, lack of LRP activity results in decreased A␤ production, whereas the presence of functional LRP is associated with increased production and secretion of A␤ (Ulery et al., 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ulery et al., 2000 source

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

    Interpretationreasoning

    Decreased expression of other receptors in the RAP-/- mice might also play a role increasing Aβ deposition.

    “Thus, we cannot completely rule out the possibility that decreased expression of other receptors in the RAPϪ/Ϫ mice might also play a role increasing A␤ deposition.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    These effects were blocked by exogenous administration of RAP and are dependent on calcium/calmodulin-dependent kinase 2 signaling.

    “These effects were blocked by exogenous administration of RAP and are dependent on calcium/calmodulin-dependent kinase 2 signaling (Van Uden et al., 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Van Uden et al., 2000 source

  • Probably not a substantial claim. The authors may not put it forward as true.

    Interpretationreasoning

    The alterations observed in the hAPPtg/RAP-/- mice were probably most closely associated with altered functioning of LRP.

    “we hypothesized that the alterations observed in the hAPPtg/RAPϪ/Ϫ mice were probably most closely associated with altered functioning of LRP.”
    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

    The resulting groups of littermates contained comparable random mixtures of the C57BL/6, DBA/2, and 129 strains.

    “The resulting groups of littermates contained comparable random mixtures of the C57BL /6, DBA /2, and 129 strains.”
    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

    RAGE and SR-A mediate brain endocytosis and transcytosis of Aβ, whereas LRP mediates blood-brain barrier transport of plasma Aβ complexed to apoJ.

    “Furthermore, RAGE and SR-A mediate brain endocytosis and transcytosis of A␤, whereas LRP mediates blood-brain barrier transport of plasma A␤ complexed to apoJ (Shibata et al., 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shibata et al., 2000 source

  • It may state two separate claims as one.

    Premisecitation

    RAP-/- mice display significant age-related alterations in somatostatin-expressing neurons, accompanied by performance deficits in the water maze.

    “and display significant age-related alterations in somatostatin-expressing neurons, accompanied by performance deficits in the water maze (Van Uden et al., 1999a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Van Uden et al., 1999a

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

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

    Premisecitation

    LRP expressed by neurons has the capacity to signal and may be involved in LTP and in regulating synaptic plasticity.

    “This is consistent with previous studies showing that LRP expressed by neurons has the capacity to signal and may be involved in long-term potentiation (LTP) and in regulating synaptic plasticity (Herz and Strickland, 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Herz and Strickland, 2001 source

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

    Study design and conductnone given

    All mice used in this study were wild type for the mouse APP gene.

    “All mice used in this study were wild type for the mouse APP gene.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    The present study showed that decreased Aβ clearance in hAPP tg/RAP−/− mice results in increased amyloid deposition and dendritic damage.

    “In summary, the present study showed that decreased A␤ clearance in hAPP tg/RAPϪ/Ϫ mice results in increased amyloid deposition and dendritic damage”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Increased Aβ deposition in the hAPP tg/RAP-/- model could be the result of increased Aβ production or decreased Aβ clearance by lipoprotein receptors.

    “Increased A␤ deposition in the hAPP tg/RAPϪ/Ϫ model could be the result of increased A␤ production or decreased A␤ clearance by lipoprotein receptors.”
    Quote in the paperSubstantial claim
49 of 49

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.

  • MAP2 measurement regions differ between methods and results

    Major

    The MAP2 methods specify images from the neocortex and caudate-putamen, whereas the results say MAP2 was analyzed in the hippocampus. The described image collection does not account for the reported hippocampal measurement.

  • LRP caption points to RAP panels

    Minor

    The Figure 2 caption assigns panels I-L to LRP immunoreactivity, but its statement about reduced LRP immunoreactivity points to panels G and H, which it assigns to RAP.

  • MAP2 results cite the GFAP panel

    Minor

    The results cite Figure 4C for decreased MAP2 immunoreactivity, but the Figure 4 caption identifies panel C as GFAP and panel D as MAP2.

3 of 3

Citations

Cites

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1 of the 62 references couldn’t be matched to a known paper.

Cited by

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Related

Metadata

Authors
Van Uden, E., Mallory, M., Veinbergs, I., Alford, M., Rockenstein, E., & Masliah, E.
Affiliations
University of California San Diego (US)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2002-11-01
Volume
22
Issue
21
Pages
9298-9304
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.22-21-09298.2002
PMC
PMC6758061
OpenAlex
W2097116790
Cited by
91
References
62
Citations by year
2024: 1 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 1 · 2016: 5 · 2015: 2 · 2013: 5 · 2012: 3
FWCI
1.94
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (AG5131, AG‐18440)
  • National Institute on Aging (R37AG018440, R01AG018440, R01AG010689, P50AG005131, AG-5131, AG 18440)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
low density lipoprotein receptor-related protein, receptor-associated protein, amyloid-beta, amyloid deposition, neurodegeneration, amyloid plaques, amyloid clearance, lipoprotein receptors, neuroprotection, astrocyte activation, Alzheimer's disease
MeSH terms
Amyloid, Animals, Dendrites, Disease Models, Animal, Extracellular Space, Hippocampus, Homozygote, Humans, Immunohistochemistry, Mice, Transgenic, Microtubule-Associated Proteins, Amyloid beta-Protein Precursor, Disease Progression, Neocortex, Neurodegenerative Diseases, LDL-Receptor Related Protein-Associated Protein, 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 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-10 (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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