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Cited by 129Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis

Open access
Liao, Fan, Hori, Yukiko, Hudry, Eloise, Bauer, Adam Q., Jiang, Hong, Mahan, Thomas E., Lefton, Katheryn B., Zhang, Tony J. +7 more·2014·The Journal of Neuroscience
DOI 10.1523/jneurosci.0646-14.2014PMC PMC4028501
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Abstract

Apolipoprotein E (apoE) is the strongest known genetic risk factor for late onset Alzheimer's disease (AD). It influences amyloid-β (Aβ) clearance and aggregation, which likely contributes in large part to its role in AD pathogenesis. We recently found that HJ6.3, a monoclonal antibody against apoE, significantly reduced Aβ plaque load when given to APPswe/PS1ΔE9 (APP/PS1) mice starting before the onset of plaque deposition. To determine whether the anti-apoE antibody HJ6.3 affects Aβ plaques, neuronal network function, and behavior in APP/PS1 mice after plaque onset, we administered HJ6.3 (10 mg/kg/week) or PBS intraperitoneally to 7-month-old APP/PS1 mice for 21 weeks. HJ6.3 mildly improved spatial learning performance in the water maze, restored resting-state functional connectivity, and modestly reduced brain Aβ plaque load. There was no effect of HJ6.3 on total plasma cholesterol or cerebral amyloid angiopathy. To investigate the underlying mechanisms of anti-apoE immunotherapy, HJ6.3 was applied to the brain cortical surface and amyloid deposition was followed over 2 weeks using in vivo imaging. Acute exposure to HJ6.3 affected the course of amyloid deposition in that it prevented the formation of new amyloid deposits, limited their growth, and was associated with occasional clearance of plaques, a process likely associated with direct binding to amyloid aggregates. Topical application of HJ6.3 for only 14 d also decreased the density of amyloid plaques assessed postmortem. Collectively, these studies suggest that anti-apoE antibodies have therapeutic potential when given before or after the onset of Aβ pathology.

AI snapshot

Written from the paper’s full text.

TL;DR

In 7-month-old APP/PS1 mice with preexisting plaques, 21 weeks of anti-apoE antibody HJ6.3 modestly reduced brain Aβ plaque load, improved spatial learning, and restored resting-state functional connectivity without increasing plasma cholesterol, CAA, or CAA-associated microhemorrhage. In vivo imaging showed HJ6.3 bound plaques, prevented new plaque formation, limited growth, and occasionally cleared plaques.

Key findings

  • Chronic HJ6.3 (10 mg/kg/week for 21 weeks) reduced Aβ plaque load by ~20% in cortex and ~40% in thalamus, but not significantly in hippocampus; ThioS fibrillar plaque load was significantly reduced in cortex and by ~40% in thalamus, with no significant hippocampal change.
  • Brain apoE decreased in cortex, primarily in the 1% Triton X-100 fraction, while plasma apoE was unchanged; Aβx-40 was significantly reduced in the Triton X-100 and 5 M guanidine fractions, and plasma Aβx-40 increased by 40–60%. CD45 microglial staining load in cortex decreased by 40%.
  • HJ6.3-treated mice had shorter path lengths in place trials (treatment effect: F(1,35)=4.79, p=0.035; greatest difference at block 3, p=0.019) and showed a target-quadrant bias in the probe trial (p<0.014), whereas PBS-treated mice did not; HJ6.3-treated mice also swam more slowly in place trials (treatment effect: F(1,35)=13.51, p=0.0008). fcOIS showed improved bilateral visual cortex connectivity and increased node degree in motor, somatosensory, retrosplenial, and visual cortices.
  • Topical HJ6.3 over 14 days prevented new plaque formation, limited growth, and was associated with clearance of some plaques (contingency table p<0.0001); 91% of “absent” plaques were previously labeled with HJ6.3, and postmortem plaque number/mm² was 40% lower than anti-HA control, although plaque load and ThioS measures did not differ significantly. No effect was detected on total plasma cholesterol, CAA, or CAA-associated microhemorrhage.

Methods

  • Chronic treatment: 7-month-old female APP/PS1 mice on a B6C3 background received weekly intraperitoneal HJ6.3 (10 mg/kg) or PBS for 21 weeks; behavioral testing occurred during the last 4 weeks, followed by fcOIS, histology, and ELISA.
  • Acute imaging: HJ6.3 or anti-HA control antibody was topically applied to the cortical surface; in vivo two-photon microscopy tracked amyloid plaques at day 0 and day 14, followed by postmortem immunohistology and ThioS staining.
  • Analyses included two-tailed Student’s t tests, one-way/rmANOVA with Huynh-Feldt and Bonferroni corrections, Fisher Z transforms for fcOIS, chi-square contingency tests, Mann-Whitney tests, and mixed-effect models.

Limitations

  • Stated: the APP/PS1 mice had a relatively small amount of CAA; future studies are needed in another mouse model and in animals expressing human apoE isoforms. The study also does not rule out a role for anti-apoE antibody-mediated phagocytosis in clearing Aβ colocalized with apoE in plaques.
  • Evident: only female APP/PS1 mice were studied, and the chronic effect on established CNS amyloid was modest, with no significant hippocampal plaque reduction.
  • Evident: the acute mechanistic imaging used topical antibody application rather than the peripheral route used for chronic treatment, and HJ6.3-treated mice swam more slowly, which the authors addressed by using path length for place-trial analysis.

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

Integrity signals

Registry

Crossref · 10.1523/jneurosci.0646-14.2014

Cites

54 of 54 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

24 of 48 cited sources checked · 12 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Certain types of active and passive immunization have resulted in significant side effects such as brain edema and hemorrhages.

    “Certain types of active and passive immunization have resulted in significant side effects such as brain edema and hemorrhages (Brody and Holtzman, 2008).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Brody and Holtzman, 2008 source

      The Introduction (page unavailable) reports increased microhemorrhages in mice given certain anti-Aβ antibodies and a similar hemorrhage in one actively vaccinated patient. It also reports serious meningoencephalitis after active vaccination, but the passages found do not report brain edema. The paper cautions that the clinical significance of the mostly small hemorrhages is uncertain. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Aβ plays a key role in the development of Alzheimer's disease.

    “There is substantial evidence indicating that amyloid-␤ (A␤) plays a key role in the development of AD (Hardy and Selkoe, 2002;Lemere and Masliah, 2010).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Hardy and Selkoe, 2002 source
    • cites Lemere and Masliah, 2010 source
  • Premisecitation

    There is functional disruption in APP/PS1 mice after Aβ deposition.

    “and that there is functional disruption in APP/PS1 mice after A␤ deposition (White et al., 2011;Bero et al., 2012).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites White et al., 2011 source

      The Methods and Results describe functional-connectivity imaging in Swiss Webster mice, not APP/PS1 mice. The Discussion proposes imaging Alzheimer’s disease models as a future application; our copy does not report functional disruption after Aβ deposition (searched for APP/PS1, amyloid deposition, and related terms). (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites Bero et al., 2012 source
  • Premisecitation

    14 d short-term passive immunization with HJ6.3 increased reactive microglia.

    “For apoE passive immunotherapy, we previously observed an increase of reactive microglia with a 14 d short-term passive immunization with HJ6.3 (Kim et al., 2012), suggesting the involvement of microglia in the antibody-mediated A␤ removal.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Kim et al., 2012 source

      The Results and Discussion section reports that short-term HJ6.3 treatment significantly increased CD45 staining around amyloid plaques, a marker used to assess activated microglia. But Materials and Methods describes four injections every three days, with tissue collected 24 hours after the last injection—not a 14-day treatment. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    fcOIS is a sensitive imaging modality capable of measuring functional connectivity between brain regions in healthy mice.

    “We have shown previously that fcOIS is a sensitive imaging modality capable of measuring functional connectivity between brain regions in healthy mice (White et al., 2011;Bero et al., 2012)”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites White et al., 2011 source
    • cites Bero et al., 2012 source
  • Classified as probably not a substantial claim. 26
  • May combine two claims. 24
  • The quote only partly states this claim. 1

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

    Premisecitation

    Passive immunization of APP/PS1 mice before Aβ plaque onset resulted in a strong decrease of Aβ plaques and insoluble Aβ40 and Aβ42 levels.

    “Recently, we found that passive immunization of APPswe/PS1⌬E9 (APP/PS1) mice before A␤ plaque onset resulted in a strong decrease of A␤ plaques and insoluble A␤ 40 and A␤ 42 levels (Kim et al., 2012).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Kim et al., 2012 source

      The Results and Discussion section reports a 70–80% reduction in Aβ plaque load and significant reductions in insoluble Aβ40 and Aβ42 in HJ6.3-treated APPswe/PS1ΔE9 mice (page unavailable). But it says treatment began when the mice had just started to develop amyloid deposition, not before plaque onset. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    ApoE affects Aβ accumulation by modulating both Aβ aggregation and clearance.

    “There is compelling evidence showing that apoE affects A␤ accumulation by modulating both A␤ aggregation (Ma et al., 1994;Wisniewski et al., 1994) and clearance (Sadowski et al., 2006;Deane et al., 2008;Jiang et al., 2008;Castellano et al., 2011)”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Ma et al., 1994

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

    • cites Wisniewski et al., 1994

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

    • cites Sadowski et al., 2006 source

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

    Premisecitation

    Short-term Aβ antibody administration with certain anti-Aβ antibodies increases reactive microglia whereas long-term administration decreases reactive microglia.

    “This time-dependent change in microglial activation agrees with the pattern observed with A␤ passive immunization, in which short-term A␤ antibody administration with certain anti-A␤ antibodies increases reactive microglia whereas long-term administration decreases reactive microglia (Wilcock et al., 2003;Wilcock et al., 2004b).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Wilcock et al., 2003 source

      The Results report increased microglial activation 72 hours after anti-Aβ antibody injection, while the Abstract says activation returned to control levels at one week. This supports a rise followed by a decline, but the study followed a single intracranial injection rather than comparing short-term with long-term antibody administration; it also found no observable activation at the earlier 24-hour time point. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Wilcock et al., 2004b

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

  • May combine two claims.

    Findingown data

    Bilateral functional connectivity in the HJ6.3 group appeared more globally restored and resembled that of healthy wild-type mice.

    “Compared with PBS-treated mice, bilateral functional connectivity in the HJ6.3 group appeared to be more globally restored and to resemble that of healthy, wild-type mice (Fig. 7C), as described previously (White et al., 2011;Bero et al., 2012).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites White et al., 2011 source
    • cites Bero et al., 2012 source

      The Results sections on functional connectivity disruption and local Aβ deposition report bilateral connectivity measurements in wild-type and APP/PS1 mice, providing a basis for the wild-type comparison. They do not report HJ6.3 or PBS treatment, so this paper does not support the claimed restoration in the HJ6.3 group. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Decreasing the apoE level by overexpressing low-density lipoprotein receptor results in decreased amyloidosis.

    “Conversely, blocking the interaction between apoE and A␤ (Sadowski et al., 2006) and decreasing the apoE level by overexpressing low-density lipoprotein receptor (Kim et al., 2009) or haploinsufficiency of apoE (Bales et al., 1999;Holtzman et al., 2000;Kim et al., 2011;Bien-Ly et al., 2012) results in decreased amyloidosis.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Kim et al., 2009 source

  • Classified as probably not a substantial claim.

    Premisecitation

    ApoE plays a key role in CAA development.

    “Although apoE is known to play a key role in CAA development (Holtzman et al., 2000;Fryer et al., 2003), therapeutic antibodies targeting apoE may induce fewer or no side effects associated with CAA.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Holtzman et al., 2000

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

    • cites Fryer et al., 2003 source

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

    Premisecitation

    For certain Aβ antibodies such as m266, increases of peripheral Aβ have been observed because antibody prevented Aβ from being degraded via binding to it and potentially increasing net Aβ efflux out of the brain.

    “For certain A␤ antibodies, such as m266, increases of peripheral A␤ has been observed because antibody prevented A␤ from being degraded via binding to it and potentially increasing net A␤ efflux out of the brain (DeMattos et al., 2002;Yamada et al., 2009).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites DeMattos et al., 2002 source
    • cites Yamada et al., 2009 source

      The Introduction reports that m266 increased plasma Aβ and describes reduced clearance of antibody-bound Aβ as an explanation, though it does not establish that binding prevented degradation specifically. The proposed increase in brain-to-blood efflux is not supported by this study: the Discussion reports that m266 instead retarded efflux. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Expression of apoE3 and apoE4 in the mouse brain results in diminished efflux of Aβ into the blood compared with apoE2.

    “Expression of apoE3 and apoE4 in the mouse brain results in diminished efflux of A␤ into the blood compared with apoE2 (Hudry et al., 2013).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Hudry et al., 2013 source

      The Results section reports lower plasma Aβ40 in mice expressing APOE3 or APOE4 than in those expressing APOE2 and says this suggests greater retention of Aβ in the CNS. The paper therefore supports the direction of the comparison, but diminished efflux is an inference from plasma concentrations, not a directly measured result. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

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

    Premisecitation

    LXR agonists decrease Aβ deposition in the brain while modestly increasing apoE expression.

    “LXR agonists have been shown to decrease A␤ deposition in the brain while modestly increasing apoE expression (Koldamova et al., 2005;Zelcer et al., 2007;Fitz et al., 2010).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Koldamova et al., 2005 source

      The in vivo results report reduced soluble Aβ40 and Aβ42 in the brains of T0901317-treated APP23 mice, but do not establish reduced Aβ deposition. The in vivo results and Discussion report no significant change in brain apoE protein, rather than a modest increase. Page numbers are unavailable in our copy. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites Zelcer et al., 2007 source

      The Results report that loss of LXR increased cortical Aβ plaques in APP/PS1 mice, but this is not a demonstration that agonist treatment decreased brain Aβ deposition. The Results also state that Apoe mRNA was not induced by LXR ligand treatment, contrary to the claimed increase in expression; Apoe protein was lower in LXR-null mice. Page numbers were not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Fitz et al., 2010 source

      The Results report reduced amyloid plaque load after LXR agonist treatment in APP23 mice on a high-fat diet. In the Results section on Abca1 and ApoE, ApoE protein increased approximately twofold, while the 15% increase in Apoe mRNA was not statistically significant. Thus the paper supports increased ApoE protein, but not an unqualified claim of a modest increase in ApoE expression. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    HJ6.3 treatment resulted in a 40-60% increase in plasma Aβx-40 without affecting apoE levels.

    “In plasma, HJ6.3 treatment resulted in a 40 -60% increase in A␤ x-40 without affecting apoE levels (Fig. 4B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    HJ6.3-treated mice showed a spatial bias for the target quadrant, spending significantly more time in the target quadrant than in each other quadrant, whereas PBS-treated mice did not show a spatial bias for the target quadrant.

    “The HJ6.3-treated mice did, however, show a spatial bias for the target quadrant (Fig. 6C) in that they spent significantly more time in the target quadrant relative to the times they spent in each of the other quadrants ( p Ͻ 0.014), whereas the PBS-treated group did not show a spatial bias for the target quadrant.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    56% of stable plaques were also bound by HJ6.3, but the ratio of plaque size of these deposits decreased between 0 and 14 d, a change not observed with nonlabeled plaques or with the anti-HA control antibody.

    “At the same time, 56% of”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    DyLight 594-HJ6.3 can bind small, methoxy-XO4-negative nonfibrillar plaques as well as methoxy-XO4-positive fibrillar plaques.

    “Immunohistochemistry showed that DyLight 594-HJ6.3 can also bind small, methoxy-XO 4 -negative nonfibrillar plaques, as well as methoxy-XO 4 -positive fibrillar plaques (Fig. 10B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    APP/PS1 mice treated with HJ6.3 exhibited improved bilateral functional correlation strength in visual cortex, with trends toward improvement in motor and somatosensory cortices.

    “APP/ PS1 mice treated with HJ6.3 exhibited improved bilateral functional correlation strength in visual cortex with trends toward improvement in motor and somatosensory cortices (Fig. 7 A, B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Peripheral weekly administration of apoE antibodies into mice with preexisting Aβ plaques attenuates plaque load and insoluble Aβ.

    “In the present study, we report that peripheral weekly administration of apoE antibodies into mice with preexisting A␤ plaques attenuates plaque load and insoluble A␤ without causing significant side effects such as hypercholesterolemia, CAA, or CAAassociated microhemorrhage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HJ6.3 treatment decreased apoE primarily in the 1% Triton X-100 fraction of brain tissue lysates, with no alteration in the PBS and 5 M guanidine fractions.

    “Biochemical analysis of apoE in the brain tissue lysates demonstrated that apoE was decreased primarily in the 1% Triton X-100 fraction, whereas the levels in the PBS and 5 M guanidine fraction were unaltered (Fig. 4A, top).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    HJ6.3 can bind directly to intraparenchymal amyloid deposits and to CAA.

    “We confirmed that the anti-apoE antibody HJ6.3 can bind directly to intraparenchymal amyloid deposits and to CAA (Fig. 10A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The groups did not differ in probe trial platform crossings or time spent in the target quadrant.

    “Analysis of the probe trial data indicated that the groups did not differ in terms of platform crossings (data not shown) or time spent in the target quadrant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    When peripherally administrated into mice with preexisting Aβ deposition, the anti-apoE antibody HJ6.3 was able to improve spatial learning performance and functional connectivity in addition to its effects on Aβ pathology.

    “Importantly, when peripherally administrated into mice with preexisting A␤ deposition, the anti-apoE antibody HJ6.3 was able to improve spatial learning performance and functional connectivity in addition to its effects on A␤ pathology.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    ApoE colocalizes with Aβ plaques.

    “and it also colocalizes with A␤ plaques (Namba et al., 1991).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Namba et al., 1991 source

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

    Study design and conductcitation

    Seed placement was determined a priori using an anatomical atlas.

    “Seed placement was determined a priori using an anatomical atlas (Franklin and Paxinos, 1996).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Franklin and Paxinos, 1996

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

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

    Study design and conductnone given

    The Huynh-Feldt adjustment of α levels was used for all within-subjects effects containing more than two levels to protect against violations of sphericity/compound symmetry assumptions underlying rmANOVA models.

    “The Huynh-Feldt adjustment of ␣ levels was used for all withinsubjects effects containing more than two levels to protect against violations of sphericity/compound symmetry assumptions underlying rmANOVA models.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All experimental protocols were approved by the Animal Studies Committee at Washington University, Massachusetts General Hospital Subcommittee for Research, and the Animal Care and Use Committee at Harvard Medical School.

    “All experimental protocols were approved by the Animal Studies Committee at Washington University, Massachusetts General Hospital Subcommittee for Research, and the Animal Care and Use Committee at Harvard Medical School.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The ε4 allele of apolipoprotein E is the strongest genetic risk factor for late-onset Alzheimer's disease.

    “The ␧4 allele of apolipoprotein E (apoE) has been established as the strongest genetic risk factor for late-onset AD (Corder et al., 1993;Strittmatter et al., 1993a;Strittmatter et al., 1993b;Corder et al., 1994;Belinson and Michaelson, 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Corder et al., 1993 source
    • cites Strittmatter et al., 1993a

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

    • cites Strittmatter et al., 1993b

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

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

    Study design and conductown data

    Results of plaque load were analyzed using a nonparametric Mann-Whitney test because the data did not follow a normal distribution.

    “Results of plaque load were analyzed using a nonparametric Mann-Whitney test because the data did not follow a normal distribution (according to the D'Agostino and Pearson test).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Data from all mice were subjected to an initial quality check before spectroscopic analysis, and data runs with temporal variation in reflected light level intensity exceeding 1% for any wavelength were excluded.

    “Data from all mice were subjected to an initial quality check before spectroscopic analysis.Data runs (5 min) in which temporal variation in reflected light level intensity exceeded 1% for any wavelength were excluded from further analysis.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Laser power was measured and adjusted before each imaging, and the settings of the photomultiplier tubes were maintained unchanged throughout the different imaging sessions.

    “The laser power was measured and adjusted before each imaging and the settings of the photomultiplier tubes were maintained unchanged throughout the different imaging sessions.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Microglial-mediated phagocytosis is one of the major mechanisms for removal of plaques in response to some anti-Aβ antibodies.

    “One of the major mechanisms for removal of the plaques in response to some anti-A␤ antibodies is microglial-mediated phagocytosis (Bard et al., 2000;Demattos et al., 2012).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bard et al., 2000 source
    • cites Demattos et al., 2012 source

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

    Study design and conductreasoning

    To ensure comparisons were performed only on the brain area visualized in all mice, the intersection of each brain mask was calculated and made symmetric.

    “To ensure that all comparisons were performed only on the brain area visualized in all mice, the intersection of each brain mask was calculated and made symmetric.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    ApoE colocalizes with newly formed Aβ deposits.

    “Previous work has shown that apoE colocalizes with newly formed A␤ deposits and that apoE4 carriers show more apoE containing newly formed plaques than individuals with other apoE genotypes, suggesting the involvement of apoE in the initiation of plaque formation (Thal et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Thal et al., 2005 source

  • Classified as probably not a substantial claim.

    Premisecitation

    In previous studies of active and passive immunization involving generation of certain anti-Aβ antibodies, an increase of CAA and CAA-associated microhemorrhage has been observed.

    “In previous studies of active and passive immunization involving the generation of certain anti-A␤ antibodies, an increase of CAA and CAA-associated microhemorrhage has been observed (Pfeifer et al., 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pfeifer et al., 2002 source

  • May combine two claims.

    Interpretationown data

    HJ6.3 prevents new plaque formation, inhibits Aβ plaque growth, favors the clearance of amyloid aggregates, and improves brain function.

    “The results suggest that HJ6.3 prevents new plaque formation, inhibits A␤ plaque growth, favors the clearance of amyloid aggregates, and improves brain function.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Aβ metabolism is regulated by Aβ-binding proteins.
    • Rests on an assumption: Seven-month-old APP/PS1 mice have preexisting Aβ plaques.

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

    Interpretationcitation

    ApoE is involved in the initiation of plaque formation.

    “Previous work has shown that apoE colocalizes with newly formed A␤ deposits and that apoE4 carriers show more apoE containing newly formed plaques than individuals with other apoE genotypes, suggesting the involvement of apoE in the initiation of plaque formation (Thal et al., 2005).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The anti-apoE antibody HJ6.3 targeted apoE associated with brain lipids and suppressed amyloidosis.

    “Our observation suggests the possibility that the anti-apoE antibody HJ6.3 targeted apoE associated with brain lipids and suppressed amyloidosis.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The lack of CAA increase may be due to the anti-apoE antibody enhancing both apoE and Aβ clearance, but via a different mechanism from certain Aβ antibodies that favor Aβ clearance but may enhance Aβ transport along the interstitial fluid surrounding arterioles where CAA forms.

    “This may be due to the anti-apoE antibody enhancing both apoE and A␤ clearance, but via a different mechanism from certain A␤ antibodies that favor A␤ clearance but may enhance A␤ transport along the interstitial fluid surrounding arterioles where CAA forms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    HJ6.3 may be enhancing Aβ transport across the BBB or enhancing its CSF/ISF to plasma flow via decreasing the apoE level or sequestering apoE.

    “In the present study, HJ6.3 may be enhancing A␤ transport across the BBB or enhancing its CSF/ISF to plasma flow via decreasing the apoE level or sequestering apoE.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    ApoE4 carriers show more apoE containing newly formed plaques than individuals with other apoE genotypes.

    “Previous work has shown that apoE colocalizes with newly formed A␤ deposits and that apoE4 carriers show more apoE containing newly formed plaques than individuals with other apoE genotypes, suggesting the involvement of apoE in the initiation of plaque formation (Thal et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Thal et al., 2005 source

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

    Premisecitation

    Overexpression of an apoE receptor, a low-density lipoprotein receptor, lowers the brain apoE level and enhances the rate of brain-to-blood transportation of Aβ.

    “Overexpression of an apoE receptor, a low-density lipoprotein receptor, lowers the brain apoE level and enhances the rate of brain-toblood transportation of A␤ (Castellano et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Castellano et al., 2012 source

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    The increase of plasma Aβ could be mediated through another mechanism that is due to a central or peripheral effect.

    “Therefore, the increase of plasma A␤ could be mediated through another mechanism that is due to a central or peripheral effect.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    There is still debate regarding whether increasing or decreasing apoE is the best strategy in regard to AD therapeutics.

    “The role of apoE in AD pathogenesis has been studied extensively, but there is still debate regarding whether increasing or decreasing apoE is the best strategy in regard to AD therapeutics (Ashford, 2002;Teter et al., 2002).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Ashford, 2002 source
    • cites Teter et al., 2002 source

  • May combine two claims.

    Interpretationown data

    The anti-apoE antibody HJ6.3 is able to suppress further Aβ deposition and to enhance the clearance or shrinkage of a small percentage of plaques after antibody application if plaques are bound by the HJ6.3 antibody.

    “Collectively, our data suggest that the anti-apoE antibody HJ6.3 is able to suppress further A␤ deposition and to enhance the clearance or shrinkage of a small percentage of plaques after antibody application if plaques are bound by the HJ6.3 antibody.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    LXR agonists strongly increase apoE lipidation by increasing ABCA1 and affecting other inflammatory mechanisms.

    “However, these agents also strongly increase apoE lipidation by increasing ABCA1 and affecting other inflammatory mechanisms.”
    Quote in the paperNot a substantial claim
42 of 42

  • The paper relies on this without support.

    Aβ metabolism is regulated by Aβ-binding proteins.

    “Given that A␤ metabolism is regulated by A␤-binding proteins, immunization approaches targeted against proteins that regulate A␤ metabolism could also provide another treatment avenue, potentially with fewer side effects.”

  • The paper relies on this without support.

    Seven-month-old APP/PS1 mice have preexisting Aβ plaques.

    “Here, we treated 7-month-old APP/PS1 mice that had preexisting A␤ plaques with the anti-apoE monoclonal antibody HJ6.3 for 21 weeks.”

  • The paper relies on this without support.

    The APP/PS1 mouse model of Aβ amyloidosis is predictive of human Alzheimer's disease for evaluating anti-apoE antibody therapy.

    “Together, the data suggest that further development of anti-apoE antibodies may be warranted as a potential therapeutic strategy.”
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?

  • ApoE antibodies can suppress amyloidosis progression, alleviate amyloid pathology and improve cognitive function through multiple mechanisms including modification of glia responses, regulation of proinflammatory cytokines, amendment of apoE4-induced apoER2 reduction, and improvement of cerebrovascular function.

    “ApoE antibodies can suppress amyloidosis progression, alleviate amyloid pathology and improve cognitive function through multiple mechanisms including modification of glia responses”

    From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Liao et al 2014

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • The main effect of apoE on risk for AD is via its effect on Aβ clearance and aggregation.

    “Our studies suggest that the main effect of apoE on risk for AD is via its effect on Aβ clearance and aggregation (Castellano et al., 2011; Kim et al., 2009b; 2011; 2012a; Liao et al., 2014).”

    From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Liao et al., 2014

  • Long-term treatment with the anti-apoE antibody HJ6.3 leads to the downregulation of brain apoE levels in APP/PS1 mice.

    “long-term treatment (weekly intraperitoneal injections for 21 weeks) with the anti-apoE antibody HJ6.3 leads to the downregulation of brain apoE levels in APP/PS1 mice”

    From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Liao et al 2014

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.

  • Four bilateral regions are described, but six correlation values are reported

    Minor

    The methods name four regions-motor, somatosensory, retrosplenial, and visual cortex-each paired with its contralateral homolog. That yields four bilateral correlation values per mouse, not six.

1 of 1

Cites

Flagged first, then by citations

1 of the 55 references couldn’t be matched to a known paper.

Cited by

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Related

Authors
Liao, F., Hori, Y., Hudry, E., Bauer, A. Q., Jiang, H., Mahan, T. E., Lefton, K. B., Zhang, T. J., Dearborn, J. T., Kim, J., Culver, J. P., Betensky, R., Wozniak, D. F., Hyman, B. T., & Holtzman, D. M.
Affiliations
  • Hope Center for Neurological Disorders (US)
  • Harvard University (US)
  • Washington University in St. Louis (US)
  • Mayo Clinic (US)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2014-05-21
Volume
34
Issue
21
Pages
7281-7292
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.0646-14.2014
PMC
PMC4028501
OpenAlex
W2000809016
Semantic Scholar
562b460f7514d7aab50b83adf769f16be6142da3
Cited by
128
References
55
Citations by year
2026: 7 · 2025: 10 · 2024: 7 · 2023: 4 · 2022: 13 · 2021: 12 · 2020: 14 · 2019: 16 · 2018: 12 · 2017: 10 · 2016: 13 · 2015: 6 · 2014: 4
FWCI
6.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
Funders
  • Eli Lilly and Company
  • AstraZeneca
  • BrightFocus Foundation (A2013037F)
  • Cure Alzheimer's Fund
  • National Institutes of Health (4r01ns078223-05, AG13956, R37 AG13956)
  • Genentech
  • National Institute on Aging (P30-AG062421, R37AG13956, RF1 AG047644, P50 AG 005134, R37AG013956)
  • National Institute of Neurological Disorders and Stroke (R01-NS078223)
Topics
  • Health Sciences › Medicine › Physiology › 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
apolipoprotein E, amyloid plaques, amyloid-beta deposition, Alzheimer's disease, APP/PS1 mice, immunotherapy, plaque clearance, resting-state functional connectivity, spatial learning, cerebral amyloid angiopathy, serum cholesterol
MeSH terms
Alzheimer Disease, Amyloidosis, Animals, Antibodies, Apolipoproteins E, Brain, Cholesterol, Disease Models, Animal, Female, Hemorrhage, Lameness, Animal, Mice, Transgenic, Mutation, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Maze Learning, 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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-17.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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