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Cited by 103Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

The DOI matches its Crossref record; 62 of the 62 references it cites were found in a registry or an index; 20 of the 67 sources its claims cite were checked for support.

Apolipoprotein E Receptors Mediate the Effects of β-Amyloid on Astrocyte Cultures

Open access
LaDu, Mary Jo, Shah, Javeed Ali, Reardon, Catherine A., Getz, Godfrey S., Bu, Guojun, Hu, Jingru, Guo, Ling, Van Eldik, Linda J.·2000·Journal of Biological Chemistry
DOI 10.1074/jbc.m000602200
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Abstract

We have previously shown that beta-amyloid (Abeta) induces astrocyte activation in vitro and that this reaction is attenuated by the addition of exogenous apolipoprotein E (apoE)-containing particles. However, the effects of Abeta on endogenous apoE and apoJ levels and the potential role of apoE receptors in astrocyte activation have not been addressed. Three activating stimuli (lipopolysaccharide, dibutyryl cAMP, and aged Abeta 1-42) were used to induce activation of rat astrocyte cultures, as assessed by changes in morphology and an increase in interleukin-1beta. However, only Abeta also induced approximately 50% reduction in the amount of released apoE and apoJ and an 8-fold increase in the levels of cell-associated apoE and apoJ. Experiments using two concentrations of receptor-associated protein, an inhibitor of apoE receptors with a differential affinity for the low density lipoprotein receptor (LDLR) and the LDLR-related protein (LRP), suggest that LRP mediates Abeta-induced astrocyte activation, whereas LDLR mediates the Abeta-induced changes in apoE levels. Receptor-associated protein had no effect on apoJ levels or on activation by either dibutyryl cAMP or lipopolysaccharide. These data suggest that apoE receptors translate the presence of extracellular Abeta into cellular responses, both initiating and modulating the inflammatory response induced by Abeta.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

Aged β-amyloid (Aβ 1-42) activates cultured rat astrocytes and, uniquely among the tested activators, alters endogenous apoE and apoJ levels. Receptor-associated protein (RAP) experiments suggest LRP mediates Aβ-induced astrocyte activation, whereas LDLR mediates Aβ-induced changes in apoE, with apoJ changes independent of RAP-inhibitable apoE receptors.

Key findings

  • Aβ 1-42 (10 µM), dibutyryl cAMP (1 mM), and LPS (10 µg/ml) all induced morphological activation and increased proIL-1β in rat astrocyte cultures; GFAP levels did not change.
  • Only Aβ altered endogenous apolipoproteins: cell-associated apoE and apoJ increased approximately 8-fold, while conditioned-medium apoE decreased by a mean of 35% and apoJ by 60% relative to control. The abstract describes an approximately 50% reduction in released apoE and apoJ.
  • RAP at 70 nM, which inhibits LRP but not LDLR, blocked Aβ-induced morphological activation and attenuated the Aβ-induced increase in proIL-1β, suggesting LRP mediates activation.
  • RAP at 1 µM, which inhibits both LRP and LDLR, blocked the Aβ-induced increase in cell-associated apoE and the decrease in released apoE, but 70 nM RAP did not; this suggests LDLR mediates the apoE changes. RAP did not block Aβ-induced apoJ changes, and heparin or heparan sulfate did not block the Aβ-induced increase in cell-associated apoE.

Methods

  • Primary astrocyte cultures were prepared from cerebral cortex of 1–2-day-old neonatal Harlan Sprague-Dawley rats; tertiary cultures were approximately 95–98% astrocytes with 2–5% microglial cells.
  • Cells were treated with aged Aβ 1-42 (10 µM), dbcAMP (1 mM), LPS (10 µg/ml), or control buffer. RAP (1 µM or 70 nM) was added 1 h before Aβ; heparin (100 µg/ml) and heparan sulfate (1 µM) were also tested.
  • Activation was assessed by morphology and Western blot for proIL-1β and GFAP. ApoE and apoJ protein levels in cell lysates and conditioned medium were measured by Western blot; apoE, apoJ, and IL-1β mRNA were measured by slot blot normalized to glyceraldehyde-3-phosphate dehydrogenase. Statistical significance was assessed by variance F tests and Student’s t test at p < 0.05.

Limitations

  • The paper states that the data do not address whether the Aβ/LRP pathway uses the same downstream activation signaling events as LPS and dbcAMP.
  • The paper states that the mechanism and function of Aβ-induced cell-associated apoJ accumulation are unclear, and that an unidentified apoJ receptor or other apoE receptors may be involved.
  • The paper notes that microglia may play a similar role but focuses on astrocytes; the findings are from in vitro rat astrocyte cultures, so in vivo relevance is not established in this study.

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

Integrity signals

Registry

Crossref · 10.1074/jbc.m000602200

Cites

62 of 62 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

20 of 67 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    ApoE and apoJ form stable complexes with Aβ in vitro.

    “In vitro, apoE and apoJ form stable complexes with A␤ (11, 16 -20), alter the aggregation of various A␤ peptides (21)(22)(23), and affect A␤ neurotoxicity (24 -27).”
    Quote in the paperSubstantial claim3 of 6 sources checked
    • cites [11] Strittmatter, 1993, Proc. Natl. Acad. Sci. U. S. A. source

      The paper’s in vitro binding results (section labeled Materials and Methods; page not provided) show that ApoE remained bound to immobilized Aβ peptides even after washing with 5% SDS, supporting strong, stable binding. Our copy does not report that apoJ forms complexes with Aβ, so the apoJ portion is unsupported by this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [16] Ghiso, 1993, Biochem. J. source
    • cites [17] LaDu, 1994, J. Biol. Chem. source
    • cites [18] LaDu, 1995, J. Biol. Chem. source
    • cites [19] Matsubara, 1995, J. Biol. Chem. source

      The Results describe an apoJ–Aβ1-40 complex formed in vitro, and the Abstract says that apoE isoforms could not dissociate it at physiologic concentrations. The paper also reports apoE binding to Aβ, but does not establish that apoE–Aβ complexes are themselves stable. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [20] Aleshkov, 1997, Biochem. source
  • Premisecitation

    ApoE and apoJ affect Aβ neurotoxicity.

    “In vitro, apoE and apoJ form stable complexes with A␤ (11, 16 -20), alter the aggregation of various A␤ peptides (21)(22)(23), and affect A␤ neurotoxicity (24 -27).”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [24] Miyata, 1996, Nat. Genet. source
    • cites [25] Jordán, 1998, J. Neurosci. source

      The Discussion reports that apoE3 attenuated Aβ neurotoxicity in primary rat hippocampal neuron cultures, supporting the apoE part of the claim. Our copy does not report an effect of apoJ on Aβ neurotoxicity; apoJ appears in a reference about Aβ aggregation and oxidative stress, which does not establish the attributed neurotoxicity effect. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [26] Oda, 1995, Exp. Neurol. source
    • cites [27] Lambert, 1998, Proc. Natl. Acad. Sci. U. S. A. source
  • Findingown data

    Activated astrocytes used in the experiments express both LDLR and LRP by immunostaining.

    “By immunostaining, these activated astrocytes express both the LDLR and LRP (data not shown), consistent with the previous observations summarized above that these are the two primary members of the LDLR family that are expressed by activated astrocytes (4 -7, 29 -31).”
    Quote in the paperSubstantial claim2 of 7 sources checked
    • cites [4] Christie, 1996, J. Neuropath. Exp. Neurol. source
    • cites [5] Pitas, 1987, J. Biol. Chem. source
    • cites [6] Rebeck, 1993, Neuron source
    • cites [7] Kim, 1996, J. Biol. Chem. source

      The Introduction says astrocytes secrete apoE, and the Discussion says LRP is expressed in brain. Neither passage addresses whether activated astrocytes express both LDLR and LRP; the paper’s receptor-expression experiments use in situ hybridization, not immunostaining of activated astrocytes. The citing sentence describes the immunostaining as its own unpublished result, so that observation cannot be verified from this source. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [29] Bu, 1994, J. Biol. Chem. source

      In the discussion of LRP expression (page unavailable), the paper reports detectable LRP mRNA in astrocytes. It does not show that activated astrocytes express both LRP and LDLR by immunostaining; its mention of LDLR concerns localization elsewhere in the central nervous system. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [30] Rebeck, 1995, Ann. Neurol. source
    • cites [31] Clatworthy, 1999, Neuroscience source
  • Premisecitation

    Neural cells express a variety of apoE receptors in the LDLR family.

    “neural cells express a variety of apoE receptors in the low density lipoprotein receptor (LDLR) family (4 -7).”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [4] Christie, 1996, J. Neuropath. Exp. Neurol. source
    • cites [5] Pitas, 1987, J. Biol. Chem. source
    • cites [6] Rebeck, 1993, Neuron source
    • cites [7] Kim, 1996, J. Biol. Chem. source
  • Premisecitation

    ApoE3 enhances neurite outgrowth in vitro by a mechanism requiring LRP.

    “Second, apoE3 enhances neurite outgrowth in vitro by a mechanism requiring LRP (32,33).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [32] Bellosta, 1995, J. Biol. Chem. source
    • cites [33] Sun, 1998, J. Neurosci. source
  • It may state two separate claims as one. 19
  • Probably not a substantial claim. 14
  • The quote only partly states this claim. 3

  • It may state two separate claims as one.

    Study design and conductcitation

    Tertiary rat astrocyte cultures are ~95-98% astrocytes, with only ~2-5% microglial cells.

    “As previously reported (37,41) these tertiary cultures are ϳ95-98% astrocytes, with only ϳ2-5% microglial cells.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [37] Hu, 1998, Brain Res. source
    • cites [41] Hu, 1996, J. Biol. Chem. source

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

    Premisecitation

    ApoE and apoJ alter the aggregation of various Aβ peptides in vitro.

    “In vitro, apoE and apoJ form stable complexes with A␤ (11, 16 -20), alter the aggregation of various A␤ peptides (21)(22)(23), and affect A␤ neurotoxicity (24 -27).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [21] Ma, 1994, Nature source
    • cites [22] Sanan, 1994, J. Clin. Invest. source

      The Discussion reports that apoE3 and apoE4 change the fibril morphology of two Aβ peptides in vitro, supporting the apoE portion of the claim. The paper does not report that apoJ alters Aβ aggregation; apoJ appears only in a reference to work on its complex with soluble Aβ. The indexed Discussion passage has no page number. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [23] Evans, 1995, Proc. Natl. Acad. Sci. U. S. A. source

      The Results (p. 3) show that apoE3 and apoE4 delayed in vitro nucleation of Aβ1–40. They also report no inhibition of Aβ1–42 under the conditions tested. Our copy does not report an effect of apoJ on Aβ aggregation, so it supports only the apoE portion of the claim. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    RAP binds LRP with affinity 3.3 nM and LDLR with Kd 250 nM.

    “The binding affinity of RAP for LRP is 3.3 nM (46), whereas the K d of RAP for the LDLR is 250 nM (47)”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [46] Iadonato, 1993, Biochem. J. source
    • cites [47] Medh, 1995, J. Biol. Chem. 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 LRP tail interacts with a GTP-binding protein, and binding of at least two LRP ligands increases intracellular cAMP levels and the activity of cAMP-dependent protein kinase.

    “Goretzki and Mueller (56) have shown that LRP tail interacts with a GTP-binding protein and that binding of at least two LRP ligands increases intracellular cAMP levels and the activity of cAMP-dependent protein kinase.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [56] Goretzki, 1998, Biochem. J. source

      The Discussion reports that two LRP ligands, lactoferrin and uPA, raise intracellular cAMP and stimulate cAMP-dependent protein kinase activity. It also describes a physical and functional association between LRP and a G-protein, but does not establish that the interaction occurs specifically at the LRP tail. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    The addition of exogenous apoE protects against Aβ-induced toxicity in neuronal cell cultures and against Aβ-induced activation of astrocyte cultures.

    “The addition of exogenous apoE protects against A␤-induced toxicity in neuronal cell cultures, as well as A␤-induced activation of astrocyte cultures (24,25,38,52,53).”
    Quote in the paperNot a substantial claim1 of 5 sources checked
    • cites [24] Miyata, 1996, Nat. Genet. source
    • cites [25] Jordán, 1998, J. Neurosci. source

      The Results (‘ApoE4 is toxic to hippocampal pyramidal neurons’) and Discussion report that added apoE3, but not apoE4, protects rat hippocampal neuronal cultures from Aβ-induced toxicity. The paper uses astrocytes as a supporting feeder layer; it does not report whether apoE protects astrocyte cultures from Aβ-induced activation. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [38] Hu, 1998, J. Neurochem. source
    • cites [52] Whitson, 1994, Biochem. Biophys. Res. Commun. source
    • cites [53] Puttfarcken, 1996, J. Neurochem. source

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

    Premisecitation

    Unregulated glial activation could potentially compromise neuronal health via the sustained secretion of pro-inflammatory cytokines and oxidative stress molecules.

    “Unregulated glial activation could potentially compromise neuronal health via the sustained secretion of pro-inflammatory cytokines and oxidative stress molecules (57,58).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [57] Smith, 1997, J. Neurosci. source

      The Discussion (page unavailable) says activated microglia can produce nitric oxide and suggests that microglia may contribute to oxidative damage in Alzheimer’s disease. It does not address sustained secretion of pro-inflammatory cytokines or establish that unregulated glial activation is the cause of the neuronal damage described. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [58] Wallace, 1997, Exp. Neurol. source

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

    Premisecitation

    ApoE, apoJ, and α2-macroglobulin have been shown to form a complex with Aβ that may facilitate clearance of the peptide.

    “ApoE, apoJ, and most recently ␣ 2 -macroglobulin have been shown to form a complex with A␤ that may facilitate clearance of the peptide (25-27, 50, 51).”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [25] Jordán, 1998, J. Neurosci. source

      The paper reports an apoE3–Aβ complex in neuronal culture medium and, in the Discussion, proposes that binding may help clear Aβ. It does not establish the same clearance mechanism for apoJ or α2-macroglobulin; the apoJ complex appears only in a cited reference, and α2-macroglobulin is mentioned as a receptor name. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [26] Oda, 1995, Exp. Neurol. source
    • cites [27] Lambert, 1998, Proc. Natl. Acad. Sci. U. S. A. source
    • cites [50] Beffert, 1998, J. Neurochem. source
    • cites [51] Narita, 1997, J. Neurochem. source

  • The quote only partly states this claim.

    Findingown data

    1 μM RAP does not inhibit dbcAMP- or LPS-induced activation.

    “Treatment of cells with 1 M RAP did not inhibit dbcAMP-or LPS-induced activation (data not shown)”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    1 μM RAP blocks Aβ-induced decrease in apoE in conditioned medium of rat astrocyte cultures.

    “In contrast, 1 M RAP blocked both the increase in cell-associated apoE (Fig. 5B) and the decrease in apoE in the conditioned medium (Fig. 5E).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    1 μM RAP blocks Aβ-induced increase in cell-associated apoE in rat astrocyte cultures.

    “In contrast, 1 M RAP blocked both the increase in cell-associated apoE (Fig. 5B) and the decrease in apoE in the conditioned medium (Fig. 5E).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Both 1 μM and 70 nM RAP attenuate Aβ-induced increase in proIL-1β levels in rat astrocyte cultures.

    “and attenuated the A␤-induced increase in proIL-1␤ levels (Fig. 4, C and D).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Aβ1-42, dbcAMP, and LPS each increase proIL-1β levels in cultured rat astrocytes.

    “cells treated with A␤, dbcAMP, or LPS exhibited an increase in proIL-1␤ levels compared with PBS-treated cells.”
    • Also stated in: § RESULTS · boosted
      “These data demonstrate that cultured rat astrocytes can be activated by A␤, dbcAMP, and LPS.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    dbcAMP and LPS do not alter cell-associated apoE or apoJ levels in rat astrocyte cultures.

    “Neither dbcAMP nor LPS altered the levels of cellassociated apoE and apoJ (Fig. 2, A and B) or the levels of apoE in the conditioned medium (Fig. 2C).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Both 1 μM and 70 nM RAP block Aβ-induced morphological activation in rat astrocyte cultures.

    “We found that both concentrations of RAP blocked A␤-induced morphological activation (Fig. 4, A and B)”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    ApoE receptors translate the presence of extracellular Aβ into cellular responses, both initiating and modulating the inflammatory response induced by Aβ.

    “These data suggest that apoE receptors translate the presence of extracellular A␤ into cellular responses, both initiating and modulating the inflammatory response induced by A␤.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Rat astrocytes secrete high density lipoprotein-like lipoprotein particles with apoE and apoJ as primary protein components.

    “We have previously reported (3) that rat astrocytes secrete high density lipoprotein-like lipoprotein particles with apoE and apoJ as the primary protein components.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] LaDu, 1998, J. Neurochem. source

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

    Study design and conductown data

    The bovine serum albumin-only control had no effect on the activation state of the cells in either the presence or the absence of Aβ.

    “The bovine serum albumin-only control had no effect on the activation state of the cells in either the presence or the absence of A␤ (data not shown).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Aged Aβ1-42 is a mixture of fibrils and soluble globular aggregates, active to astrocytes and toxic to neurons.

    “A␤ 1-42 aged according to this protocol is a mixture of fibrils and soluble globular aggregates, and is active to astrocytes (37,38) and toxic to neurons (26,27).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [37] Hu, 1998, Brain Res. source
    • cites [38] Hu, 1998, J. Neurochem. source
    • cites [26] Oda, 1995, Exp. Neurol. source
    • cites [27] Lambert, 1998, Proc. Natl. Acad. Sci. U. S. A. source
    • Rests on an assumption: The effects of the aged Aβ1-42 preparation on astrocytes are attributable to Aβ and not to other components or contaminants in the preparation.

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

    Premisecitation

    Polymorphisms in LRP or α2-macroglobulin increase the risk of late onset familial AD.

    “genetic evidence suggests that polymorphisms in either LRP or ␣ 2 -macroglobulin increase the risk of late onset familial AD (35,36).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Kang, 1997, Neurology source
    • cites [36] Blacker, 1998, Nat. Genet. source

  • Probably not a substantial claim.

    Premisecitation

    LRP mediates endocytosis of a secreted form of amyloid precursor protein.

    “LRP has been shown to mediate the endocytosis of a secreted form of amyloid precursor protein (34).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Kounnas, 1995, Cell source

  • It may state two separate claims as one.

    Interpretationreasoning

    Aβ-induced changes in cultured astrocytes involve both a novel mechanism of action and a unique set of responses.

    “A␤-induced changes in cultured astrocytes appear to involve both a novel mechanism of action and a unique set of responses.”
    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

    Glia, in particular astrocytes, are the primary cell type in the central nervous system that synthesize apoE, whereas apoJ is expressed by glia and neurons.

    “Glia, in particular astrocytes, are the primary cell type in the central nervous system that synthesize apoE, whereas apoJ is expressed by glia and neurons (reviewed in Ref. 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] LaDu, 2000, Ann. N. Y. Acad. Sci. source

  • It may state two separate claims as one.

    Interpretationown data

    Both LRP and LDLR can translate the presence of extracellular Aβ into cellular responses.

    “These data suggest that both LRP and the LDLR can translate the presence of extracellular A␤ into cellular responses (Fig. 7).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    The secretion of apoE into the extracellular space appears to reduce the functional activity of the Aβ peptide, possibly via the formation of an apoE·Aβ complex that is avidly cleared by apoE receptors, resulting in an overall increase in cell-associated apoE.

    “The secretion of apoE into the extracellular space appears to reduce the functional activity of the A␤ peptide, possibly via the formation of an apoE⅐A␤ complex that is avidly cleared by apoE receptors, resulting in an overall increase in cell-associated apoE.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The C terminus of LRP binds to two cytosolic adapter proteins, FE65 and mammalian Disabled.

    “Herz and co-workers (55) have demonstrated that the C terminus of LRP binds to two cytosolic adapter proteins, FE65 and mammalian Disabled, an observation consistent with a signaling function for the cytosolic portion of the receptor.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Trommsdorff, 1998, J. Biol. Chem. source

  • It may state two separate claims as one.

    Interpretationreasoning

    The actual amount of apoE increases in activated astrocytes, possibly via an Aβ-activated signaling mechanism linked to the LDLR.

    “This suggests that the actual amount of apoE increases, possibly via an A␤-activated signaling mechanism linked to the LDLR.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    Recent evidence suggests that apoE receptors may have a signal transduction capacity.

    “recent evidence suggests that apoE receptors may have a signal transduction capacity as well.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    The LDLR may be linked to an intracellular pathway that signals an increase in apoE translation and/or a decrease in degradation.

    “This suggests that the LDLR may be linked to an intracellular pathway that signals an increase in apoE translation and/or a decrease in degradation (steady-state apoE mRNA levels do not change).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    The LDLR mediates the Aβ-induced increase in cell-associated apoE and the decrease in apoE in the conditioned medium.

    “The LDLR mediates the A␤-induced increase in cell-associated apoE and the decrease in apoE in the conditioned medium.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisenone given

    Several reports suggest that apoE receptors may be involved in modifying the activity of Aβ in neural cells.

    “Several reports suggest that apoE receptors may be involved in modifying the activity of A␤ in neural cells.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    A recent report linked two members of the LDLR receptor family, the very LDLR and ER2, to signal transduction pathways in the central nervous system.

    “For example, a recent report linked two members of the LDLR receptor family, the very LDLR and ER2, to signal transduction pathways in the central nervous system (54).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Trommsdorff, 1999, Cell source

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

  • It may state two separate claims as one.

    Interpretationreasoning

    LRP mediates Aβ-induced changes in astrocyte morphology and increased expression of IL-1β.

    “LRP mediates A␤-induced changes in astrocyte morphology and increased expression of IL-1␤.”
    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

    ApoE3 but not apoE4 protects against Aβ-induced neurotoxicity of rat hippocampal neurons, a process inhibited by 1 M RAP.

    “For example, apoE3 but not apoE4 protects against A␤-induced neurotoxicity of rat hippocampal neurons, a process inhibited by 1 M RAP (25).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Jordán, 1998, J. Neurosci. source
33 of 33

  • The paper relies on this without support.

    The effects of the aged Aβ1-42 preparation on astrocytes are attributable to Aβ and not to other components or contaminants in the preparation.

    “A␤ 1-42 aged according to this protocol is a mixture of fibrils and soluble globular aggregates, and is active to astrocytes (37,38) and toxic to neurons (26,27).”

  • The paper relies on this without support.

    RAP specifically inhibits apoE receptors (LRP/LDLR) without affecting other pathways, so RAP-sensitive effects can be attributed to apoE receptors.

    “RAP blocks A␤-induced astrocyte activation.”
    “The A␤-stimulated changes in apoJ persist in the presence of 1 M RAP and the changes in apoE persist in the presence of 70 nM RAP, both treatments that block morphological activation.”

  • The paper relies on this without support.

    Cultured rat cortical astrocytes respond to Aβ in a way that models relevant astrocyte responses in vivo.

    “A␤-induced changes in cultured astrocytes appear to involve both a novel mechanism of action and a unique set of responses.”
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?

  • RAP at a concentration that inhibits ligand interaction of all LDLr family members was unable to inhibit fluo-Aβ-(1-42) uptake and transport.

    “RAP, at a concentration that has been proven to inhibit ligand interaction of all LDLr family members (40), was unable to inhibit fluo-A␤-(1-42) uptake and transport (Fig. 2D).”

    From Internalization of β-Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E (2007) · cites this paper as [40]

    In “RAP Blocks Aβ-induced Activation and Changes in apoE but Not apoJ” (page unavailable), the paper says a high RAP concentration was chosen to inhibit LRP and LDLR, the two primary LDLR-family members expressed by the astrocytes studied. It does not establish that this concentration inhibits ligand interactions with all LDLR-family members. The uptake-and-transport result is attributed to the citing paper’s own Fig. 2D, not to this source. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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.

  • Reported apoE decrease changes from 35% to approximately 50%

    Minor

    The results give a mean 35% decrease in conditioned-medium apoE after Aβ treatment, whereas the discussion describes the same decrease as approximately 50%.

  • LPS-associated apoJ change conflicts with the claim that only Aβ altered apoJ

    Minor

    The discussion says only Aβ induced alterations in apoE and apoJ, but the results report increased apoJ in conditioned medium from LPS-treated cells.

2 of 2

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Kounnas, 1994, In Vivo, 8, 343

Cited by

Sorted by citations

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Metadata

Authors
LaDu, M. J., Shah, J. A., Reardon, C. A., Getz, G. S., Bu, G., Hu, J., Guo, L., & Van Eldik, L. J.
Affiliations
  • Northwestern University (US)
  • University of Chicago (US)
  • Washington University in St. Louis (US)
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2000-10
Volume
275
Issue
43
Pages
33974-33980
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m000602200
OpenAlex
W1967940232
Semantic Scholar
ba7ae1f96517b574b777f839597b4dc65e6860de
Cited by
103
References
61
Citations by year
2025: 1 · 2024: 6 · 2023: 2 · 2021: 3 · 2018: 1 · 2017: 4 · 2016: 5 · 2014: 4 · 2013: 2 · 2012: 9
FWCI
1.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • Brain Research Foundation
  • American Health Assistance Foundation
  • National Institutes of Health (AG13939)
  • National Institute on Aging (P01AG015501, AG13939, AG16776)
  • National Eye Institute (F31EY021714)
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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
apolipoprotein E receptor, amyloid-beta, astrocyte activation, clusterin, LDL receptor, receptor-associated protein, IL-1β, lipopolysaccharide, dibutyryl cyclic AMP, neuroinflammation, Alzheimer's disease
MeSH terms
Animals, Apolipoproteins E, Astrocytes, Cells, Cultured, Glycoproteins, Interleukin-1, Receptors, Immunologic, Receptors, LDL, Amyloid beta-Peptides, Rats, Sprague-Dawley, Receptors, Lipoprotein, Molecular Chaperones, Low Density Lipoprotein Receptor-Related Protein-1, Clusterin, Rats

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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