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Cited by 14Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index; 5 of the 43 sources its claims cite were checked for support.

Receptor-Associated Protein (RAP) Plays a Central Role in Modulating Aβ Deposition in APP/PS1 Transgenic Mice

Open access
Xu, Guilian, Karch, Celeste, Li, Ning, Lin, Nianwei, Fromholt, David, Gonzales, Victoria, Borchelt, David R.·2008·PLoS ONE
DOI 10.1371/journal.pone.0003159PMC PMC2522286
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Abstract

BACKGROUND: Receptor associated protein (RAP) functions in the endoplasmic reticulum (ER) to assist in the maturation of several membrane receptor proteins, including low density lipoprotein receptor-related protein (LRP) and lipoprotein receptor 11 (SorLA/LR11). Previous studies in cell and mouse model systems have demonstrated that these proteins play roles in the metabolism of the amyloid precursor protein (APP), including processes involved in the generation, catabolism and deposition of beta-amyloid (Abeta) peptides. METHODOLOGY/PRINCIPAL FINDINGS: Mice transgenic for mutant APPswe and mutant presenilin 1 (PS1dE9) were mated to mice with homozygous deletion of RAP. Unexpectedly, mice that were homozygous null for RAP and transgenic for APPswe/PS1dE9 showed high post-natal mortality, necessitating a shift in focus to examine the levels of amyloid deposition in APPswe/PS1dE9 that were hemizygous null for RAP. Immunoblot analysis confirmed 50% reductions in the levels of RAP with modest reductions in the levels of proteins dependent upon RAP for maturation [LRP trend towards a 20% reduction ; SorLA/LR11 statistically significant 15% reduction (p<0.05)]. Changes in the levels of these proteins in the brains of [APPswe/PS1dE9](+/-)/RAP(+/-) mice correlated with 30-40% increases in amyloid deposition by 9 months of age. CONCLUSIONS/SIGNIFICANCE: Partial reductions in the ER chaperone RAP enhance amyloid deposition in the APPswe/PS1dE9 model of Alzheimer amyloidosis. Partial reductions in RAP also affect the maturation of LRP and SorLA/LR11, which are each involved in several different aspects of APP processing and Abeta catabolism. Together, these findings suggest a central role for RAP in Alzheimer amyloidogenesis.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

Partial loss of receptor-associated protein (RAP) in APPswe/PS1dE9 mice increased amyloid deposition despite only modest reductions in mature LRP and SorLA/LR11. The authors conclude RAP may play a central role in Alzheimer amyloidogenesis, either through these receptors or through other pathways.

Key findings

  • Mice homozygous null for RAP and transgenic for APPswe/PS1dE9 showed high post-natal mortality; only 2 such animals reached weaning age and both died before 3 months, so the study shifted to [APPswe/PS1dE9](+/−)/RAP(+/−) mice.
  • Partial RAP loss produced about 50% less RAP protein, with LRP reduced on average 20% (trend, p<0.20) and SorLA/LR11 reduced 15% (p<0.05).
  • Amyloid burden increased in [APPswe/PS1dE9](+/−)/RAP(+/−) mice: hippocampal silver-stained plaques averaged 13.5 versus 8.1 in parental line 85 mice (p<0.05), and filter-trap assays showed about twice as much high-molecular-weight Aβ (p<0.025).
  • The paper reports 30–40% increases in amyloid deposition by 9 months of age and describes the increase as 1.5- to 2-fold.

Methods

  • APPswe/PS1dE9-Line 85 mice were crossed to RAP knockout mice; because [APPswe/PS1dE9](+/−)/RAP(−/−) mice died, analyses compared [APPswe/PS1dE9](+/−)/RAP(+/−) mice with parental APPswe/PS1dE9 mice wild-type for RAP.
  • Amyloid burden was measured histologically by Bielschowsky silver staining and counting plaques in 6 sagittal hippocampal sections from 7 male [APPswe/PS1dE9](+/−)/RAP(+/−) mice and 6 parental male APPswe/PS1dE9 mice, and biochemically by filter-trap assay for high-molecular-weight Aβ.
  • Western blots measured RAP, LRP, SorLA/LR11, and APP levels; statistical comparisons used two-tailed t-tests.

Limitations

  • The paper states that the compared mice had slightly different genetic backgrounds: RAP knockout mice were congenic on C57BL/6J, while parental APPswe/PS1dE9 mice were C57BL/6J × C3H/HeJ hybrids; prior work suggested transfer to C57BL/6J may modestly delay amyloid deposition and could have attenuated the observed effect.
  • The paper states that the cause of lethality in RAP(−/−) mice co-expressing APPswe/PS1dE9 is unknown, preventing analysis of complete RAP deficiency with the transgene.
  • The paper states that whether modest reductions in LRP or SorLA/LR11 account for increased amyloid burden is unclear, and RAP may act through other undefined pathways; evident from the text, sample sizes were small (n=6–7 per group) and the main analyses used male mice only.

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

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0003159

Cites

46 of 46 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

5 of 43 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    RAP regulates other members of the LRP family, such as LRP1B, SorLA/LR11, LDL-R and VLDL-R.

    “RAP also regulates other members of the LRP family, such as LRP1B [17], SorLA/LR11[45], LDL-R and VLDL-R [46]”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [17] JA Cam, 2004, The Low Density Lipoprotein Receptor-related Protein 1B Retains beta-Amyloid Precursor Protein at the Cell Surface and Reduces Amyloid-beta Peptide Production., J Biol Chem source
    • cites [45] L Jacobsen, 1996, Molecular characterization of a novel human hybrid-type receptor that binds the alpha2-macroglobulin receptor-associated protein., J Biol Chem source

      The Results section shows that RAP binds sorLA-1. The Abstract proposes that RAP may protect sorLA from aggregation, but does not establish the regulatory effect stated as fact. Citation [45] is attached to SorLA/LR11, so the other receptors in the sentence are not assessed here. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [46] I Veinbergs, 2001, Role of apolipoprotein E receptors in regulating the differential in vivo neurotrophic effects of apolipoprotein E., Exp Neurol source
  • Findingown data

    Mice harboring one disabled RAP allele produced about 50% less RAP protein.

    “As expected, mice harboring one disabled RAP allele produced about 50% less RAP protein (Figs. 3A and B).”
    • Also stated in: § Methodology/Principal Findings · plain
      “Immunoblot analysis confirmed 50% reductions in the levels of RAP with modest reductions in the levels of proteins dependent upon RAP for maturation”
    Quote in the paperSubstantial claim
  • Findingown data

    Partial reduction of RAP with co-expression of PS1dE9 has little impact on the levels of mature LRP.

    “Moreover, partial reduction of RAP with co-expression of PS1dE9 also has little impact on the levels of mature LRP.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Co-expression of PS1dE9 with partial reductions in RAP did not lead to more robust reductions in the levels of mature LRP.

    “Surprisingly, the co-expression of PS1dE9 with partial reductions in RAP did not lead to more robust reductions in the levels of mature LRP (Fig. 4, lanes 2, 4, 5, 8, and 9 compared to lanes 1 and 3).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The difference in amyloid burden between [APPswe/PS1dE9](+/−)/RAP(+/−) and parental line 85 mice had a low probability of resulting from random chance (p<0.05).

    “Statistical analyses of the data estimated the difference in amyloid burden between the two genotypes has a low probability of resulting from random chance (<0.05).”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim. 21
  • It may state two separate claims as one. 16

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

    Interpretationown data

    Our work replicates and extends a previous study by van Uden and colleagues.

    “As outlined in the Introduction, our work replicates and extends a previous study by van Uden and colleagues [28].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [28] E Van Uden, 2002, Increased extracellular amyloid deposition and neurodegeneration in human amyloid precursor protein transgenic mice deficient in receptor-associated protein., J Neurosci source

  • It may state two separate claims as one.

    Premisecitation

    The transgene product in the LRP-minireceptor study was not full-length LRP and the transgene was not expressed by its endogenous promoter.

    “However, the transgene product was not full-length LRP and the transgene was not expressed by its endogenous promoter.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [24] CV Zerbinatti, 2004, Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein., Proc Natl Acad Sci U S A source

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

    Premisecitation

    LRP-deficient cells secrete less Aβ and restoring LRP function substantially increases Aβ production.

    “LRP-deficient cells secrete less Aβ and restoring LRP function substantially increases Aβ production [15].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [15] PG Ulery, 2000, Modulation of beta-amyloid precursor protein processing by the low density lipoprotein receptor-related protein (LRP). Evidence that LRP contributes to the pathogenesis of Alzheimer's disease., J Biol Chem source

  • Probably not a substantial claim.

    Premisecitation

    Complete deficiency in SorLA/LR11 causes a 30% increase in the secretion of mouse Aβ40 and 42.

    “In previous studies, complete deficiency in SorLA/LR11 was shown to cause a 30% increase in the secretion of mouse Aβ40 and 42 [35].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [35] OM Andersen, 2005, Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein., Proc Natl Acad Sci U S A source

      The Results report that mice lacking sorLA had approximately 30% higher murine Aβ40 and Aβ42 levels than controls. Those measurements came from cortical brain extracts, however, and do not establish a 30% increase in secretion. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Findingown data

    Levels of LRP were reduced on average 20% in [APPswe/PS1dE9](+/−)/RAP(+/−) mice, but variability reduced statistical significance to a trend (p<0.20).

    “On average, the levels of LRP were reduced 20%, but variability between animals reduced statistical significance to only a trend (p<0.20).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingcitation

    Brains of mice lacking RAP expression showed marked reductions in mature endoproteolytically processed LRP (85 KDa) with higher levels of immature LRP.

    “As previously reported in the literature [28], the brains of mice lacking the expression of RAP showed marked reductions in the levels of mature endoproteolytically processed LRP (85 KDa) with higher levels of immature LRP (Fig. 4, lanes 6 and 7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] E Van Uden, 2002, Increased extracellular amyloid deposition and neurodegeneration in human amyloid precursor protein transgenic mice deficient in receptor-associated protein., J Neurosci source

  • It may state two separate claims as one.

    Findingown data

    APPswe/PS1dE9 mice with partial reduction in RAP showed significant amyloid burden increases with modest to slight reductions in the levels of mature SorLA/LR11 and LRP.

    “We find that APPswe/PS1dE9 mice with partial reduction in RAP showed significant amyloid burden increases with modest to slight reductions in the levels of mature SorLA/LR11 and LRP.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Either RAP possesses an activity that influences amyloidogenesis in the absence of profound effects on LRP and SorLA/LR11 maturation, or relatively modest reductions in the levels of these proteins (separately or in combination) are sufficient to cause significant changes in the rate of amyloid deposition in the APPswe/PS1dE9 model.

    “We conclude that either RAP possesses an activity that influences amyloidogenesis in the absence of profound effects on LRP and SorLA/LR11 maturation, or relatively modest reductions in the levels of these proteins (separately or in combination) are sufficient to cause significant changes in the rate of amyloid deposition in the APPswe/PS1dE9 model.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Our findings indicate that RAP plays a focal role in the biology of amyloid deposition either by regulating the maturation of proteins that modulate APP processing and Aβ metabolism, or by directly modulating other yet to be defined aspects of amyloidogenesis.

    “Our findings indicate that RAP plays a focal role in the biology of amyloid deposition either by regulating the maturation of proteins that modulate APP processing and Aβ metabolism, or by directly modulating other yet to be defined aspects of amyloidogenesis.”
    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.

    Interpretationreasoning

    Either the PS1dE9 variant of PS1 does not have the same activity towards LRP maturation as possessed by the M146L or L286V variants, or some subtle difference in the expression pattern of the PS1 transgenes in the different mouse models modulates the effects.

    “Thus, either the PS1dE9 variant of PS1 does not have the same activity towards LRP maturation as possessed by the M146L or L286V variants, or some subtle difference in the expression pattern of the PS1 transgenes in the different mouse models modulates the effects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Premisecitation

    The J9 model utilizes a mini-APP gene that can produce all three isoforms of APP: APP695, APP751 and APP770.

    “The J9 model utilizes a mini-APP gene that can produce all three isoforms of APP: APP695, APP751 and APP770 [41].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] D Games, 1995, Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein., Nature source

  • Probably not a substantial claim.

    Premisenone given

    Previous studies in cell and mouse model systems demonstrated that LRP and SorLA/LR11 play roles in the metabolism of APP, including the generation, catabolism and deposition of Aβ peptides.

    “Previous studies in cell and mouse model systems have demonstrated that these proteins play roles in the metabolism of the amyloid precursor protein (APP), including processes involved in the generation, catabolism and deposition of β-amyloid (Aβ) peptides.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Mice deficient in RAP are viable and have normal lifespans because the maturation of LRP is only partially dependent upon RAP.

    “Unlike LRP, mice deficient in RAP are viable and have normal lifespans because the maturation of LRP is only partially dependent upon RAP; neurons of RAP KO mice show 75% reductions in the levels of endoproteolytically processed, mature, LRP [26].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] TE Willnow, 1995, Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivo., Proc Natl Acad Sci U S A source

  • Probably not a substantial claim.

    Study design and conductnone given

    Amyloid deposits were counted separately by two people blinded to the genotype.

    “The hippocampus was defined and the amyloid deposits contained within were counted separately by two people blinded to the genotype.”
    • Also stated in: § Partial reduction in RAP levels increases amyloid burden · plain
      “Six sections per animal were counted by two independent assessors that were blind to the genotype of the animals.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    LRP can promote Aβ production by altering the processing of APP through interactions with the Kunitz protease inhibitor (KPI) domain (APP751 or APP770).

    “LRP can promote Aβ production by altering the processing of APP through interactions with the Kunitz protease inhibitor (KPI) domain (APP751 or APP770) [36].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] GW Rebeck, 2001, Association of membrane-bound amyloid precursor protein APP with the apolipoprotein E receptor LRP., Brain Res Mol Brain Res source

  • Probably not a substantial claim.

    Premisecitation

    Transgenic mice that overexpress an LRP-minireceptor (mLRP2) were mated to PDAPP mice in a direct test of the role of LRP in amyloidogenesis.

    “In a direct test of the role of LRP in amyloidogenesis, transgenic mice that overexpress an LRP-minireceptor, containing the ligand-binding domain II of human LRP and the region representing the transmembrane subunit including the full cytoplasmic tail (mLRP2), were mated to PDAPP mice [24].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] CV Zerbinatti, 2004, Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein., Proc Natl Acad Sci U S A source

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

    Premisecitation

    Zerbinatti et al. reported that overexpression of an LRP minireceptor in the PDAPP mouse model of AD resulted in increased levels of soluble Aβ but did not impact amyloid burden.

    “Zerbinatti et al. [24] reported that overexpression of an LRP minireceptor in the PDAPP mouse model of AD, resulted in increased levels of soluble Aβ but did not impact amyloid burden.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] CV Zerbinatti, 2004, Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein., Proc Natl Acad Sci U S A source

  • Probably not a substantial claim.

    Premisecitation

    LRP appears to mediate the clearance of Aβ that is bound to α2M or ApoE.

    “LRP also appears to mediate the clearance of Aβ that is bound to α2M or ApoE[19], [21]–[23].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [19] DE Kang, 2000, Modulation of amyloid beta-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathway., J Clin Invest source
    • cites [21] Z Qiu, 1999, Alpha2-macroglobulin enhances the clearance of endogenous soluble beta-amyloid peptide via low-density lipoprotein receptor-related protein in cortical neurons., J Neurochem source
    • cites [22] M Shibata, 2000, Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier., J Clin Invest source
    • cites [23] M Narita, 1997, Alpha2-macroglobulin complexes with and mediates the endocytosis of beta-amyloid peptide via cell surface low-density lipoprotein receptor-related protein., J Neurochem source

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

    Premisenone given

    LRP and SorLA/LR11 are each involved in several different aspects of APP processing and Aβ catabolism.

    “Partial reductions in RAP also affect the maturation of LRP and SorLA/LR11, which are each involved in several different aspects of APP processing and Aβ catabolism.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The APP695 isoform can weakly bind to LRP through cytoplasmic adaptor proteins, such as FE65.

    “Although the APP695 isoform, which lacks a KPI domain, can weakly bind to LRP through cytoplasmic adaptor proteins, such as FE65 [37]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] CU Pietrzik, 2004, FE65 Constitutes the Functional Link between the Low-Density Lipoprotein Receptor-Related Protein and the Amyloid Precursor Protein., J Neurosci source

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

    Premisecitation

    Polymorphisms in the LRP and SorLA/LR11 genes have been associated with increased risk for Alzheimer's disease.

    “Polymorphisms in the LRP and SorLA/LR11 genes have also been associated with increased risk for Alzheimer's disease [3], [4].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] DE Kang, 1997, Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer's disease., Neurology source
    • cites [4] E Rogaeva, 2007, The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease., Nat Genet source

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

    Premisecitation

    The authors reported 3-fold increases in LRP levels and found increased soluble Aβ and enhanced memory impairment in PDAPP mice, but did not find evidence of a change in amyloid loads in mice harboring both transgenes as compared to mice harboring only the PDAPP transgene.

    “The authors reported 3-fold increases in LRP levels and found increased soluble Aβ and enhanced memory impairment in PDAPP mice, but did not find evidence of a change in amyloid loads in mice harboring both transgenes as compared to mice harboring only the PDAPP transgene.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] CV Zerbinatti, 2004, Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein., Proc Natl Acad Sci U S A source

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

    Premisecitation

    Maturation of LRP to the trans-Golgi network is partially dependent upon the presence of RAP, which binds to LRP at multiple sites to block the receptor's ability to interact with its ligands.

    “Maturation of LRP to the trans-Golgi network is partially dependent upon the presence of LRP-receptor-associated protein (RAP), which binds to LRP at multiple sites to block the receptor's ability to interact with its ligands [11].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] G Bu, 1995, 39 kDa receptor-associated protein is an ER resident protein and molecular chaperone for LDL receptor-related protein., Embo J source

  • It may state two separate claims as one.

    Premisecitation

    Transfer of the APPswe and mutant PS1 transgene from the hybrid background to C57BL/6J mice modestly delays the onset of amyloid deposition to lower amyloid loads at younger ages.

    “In prior studies of mice that harbor the APPswe and mutant PS1 transgene constructs utilized here, we have noted that transfer of the transgene from the hybrid background to C57BL/6J mice modestly delays the onset of amyloid deposition to lower amyloid loads at younger ages [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] AV Savonenko, 2003, Normal cognitive behavior in two distinct congenic lines of transgenic mice hyperexpressing mutant APP SWE., Neurobiol Dis source

  • Probably not a substantial claim.

    Premisecitation

    Interactions between RAP and LRP, between LRP and APP, and between LRP and APOE, α2M, and Aβ create a complicated network by which amyloidogenesis might be regulated.

    “It is clear from the literature that interactions between RAP and LRP, between LRP and APP, and between LRP and APOE, α2M, and Aβ create a complicated network by which amyloidogenesis might be regulated.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The J9 mice used by van Uden were PDGF-hAPPSwe/Ind mice, created by Mucke and colleagues.

    “The J9 mice used by van Uden were PDGF-hAPPSwe/Ind mice, which created by Mucke and colleagues [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] L Mucke, 2000, High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation., J Neurosci source

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

    Premisereasoning

    A possible flaw in the van Uden study strategy is that some offspring could be homozygous for the APP transgene, and if over-represented in one RAP genotype, could cause error in determining the contribution of RAP to amyloid load.

    “A possible flaw in this strategy is that some offspring could be homozygous for the APP transgene (i.e. have two transgene alleles instead of one). If transgene homozygous animals were, by chance, over-represented in one of the RAP genotypes examined, then there could be error in determining the contribution of RAP to amyloid load.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The levels of mature, endoproteolytically cleaved, LRP in the murine nervous system are reduced when AD associated mutants of PS1 (M146L or L286V, expressed via the hamster prion protein gene promoter) are present.

    “It has been reported that the levels of mature, endoproteolytically cleaved, LRP in the murine nervous system are reduced when AD associated mutants of PS1 (M146L or L286V, expressed via the hamster prion protein gene promoter) are present [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] E Van Uden, 1999, Aberrant presenilin-1 expression downregulates LDL receptor-related protein (LRP): is LRP central to Alzheimer's disease pathogenesis?, Mol Cell Neurosci source

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

    Premisecitation

    Expression of PS1 variants M146L or L286V, which are linked to familial AD, cause 40% reductions in the levels of mature LRP in brain.

    “It is noteworthy that expression of PS1 variants M146L or L286V, which are linked to familial AD, also cause 40% reductions in the levels of mature LRP in brain [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] E Van Uden, 1999, Aberrant presenilin-1 expression downregulates LDL receptor-related protein (LRP): is LRP central to Alzheimer's disease pathogenesis?, Mol Cell Neurosci source
29 of 29

  • The paper relies on this without support.

    The [APPswe/PS1dE9](+/−)/RAP(+/−) mice and parental APPswe/PS1dE9-Line 85 mice differ only in RAP genotype with respect to factors affecting amyloid deposition.

    “we chose to compare the parental lines of APPswe/PS1dE9 animals, which were wild-type with respect to RAP, to F1 and F2 [APPswe/PS1dE9](+/−)/RAP(+/−) mice.”
    “The two mice without APPswe/PS1dE9 transgenes were not included in measurements so that the only difference between the two groups of animals analyzed was the number of functional RAP alleles.”

  • The paper relies on this without support.

    Findings in APPswe/PS1dE9 mice are relevant to Alzheimer amyloidogenesis in humans.

    “Together, these findings suggest a central role for RAP in Alzheimer amyloidogenesis.”
    “Partial reductions in the ER chaperone RAP enhance amyloid deposition in the APPswe/PS1dE9 model of Alzheimer amyloidosis.”

  • The paper relies on this without support.

    The antibodies used specifically detect RAP, LRP, SorLA/LR11, and APP.

    “Blots were incubated with rabbit polyclonal antibody 377 αLRP (1∶1000, gift of Dr. J. Herz, University of Texas Southwestern Medical Center, Dallas, Texas, USA), rabbit polyclonal antibody 4109 αRAP (1∶1000, also a gift of Dr. J. Herz), SorLA/LR11antibody (1∶1000; monoclonal, BD Biosciences, San Jose, CA) or 6E10 Aβ (1∶5000, monoclonal, Signet Laboratories, Dedham, MA, USA).”
3 of 3

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.

  • Plaque counts imply a 1.67-fold increase, not 1.5-fold

    Minor

    The reported mean plaque counts are 13.5 and 8.1. Their ratio is approximately 1.67, which would round to 1.7-fold at the precision used in the text.

    Reported 1.5 · recomputed 1.666667

  • Figure 4 lists four lanes for five mice

    Minor

    The Figure 4 legend says there were five APPswe/PS1dE9-positive RAP(+/−) mice but assigns them only four lanes.

  • Filter-assay offspring sample size differs

    Minor

    The Methods state that seven RAP(+/−) offspring were used for the filter assay, whereas the Figure 2 legend states that six were used.

3 of 3

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. J Herz, 1992, LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation., Cell, 71, 411, 10.1016/0092-8674(92)90511-a · DOI · Paper page

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Metadata

Authors
Xu, G., Karch, C., Li, N., Lin, N., Fromholt, D., Gonzales, V., & Borchelt, D. R.
Affiliations
  • Johns Hopkins University (US)
  • University of Florida Health (US)
  • University of Florida (US)
Corresponding author
Borchelt, David R.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2008-09-08
Volume
3
Issue
9
Pages
e3159
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0003159
PMC
PMC2522286
OpenAlex
W1978504166
Semantic Scholar
e40db37eaf99206514a4b53e169b20f981499a53
Cited by
14
References
45
Citations by year
2024: 2 · 2020: 1 · 2018: 1 · 2013: 2 · 2012: 4
FWCI
0.50
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)
Funders
Alzheimer's Association
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
receptor-associated protein, amyloid-beta deposition, Alzheimer's disease, APP/PS1 mice, APPswe, APP processing, endoplasmic reticulum chaperone, low density lipoprotein receptor-related protein, amyloidogenesis, postnatal mortality
MeSH terms
Alzheimer Disease, Animals, Cell Line, Endoplasmic Reticulum, Homozygote, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Amyloid beta-Peptides, Gene Deletion, Receptors, Lipoprotein, Low Density Lipoprotein Receptor-Related Protein-1, LDL-Receptor Related Protein-Associated Protein, Mice, Presenilin-1

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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