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Cited by 342Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels

Open access
Riddell, David R., Zhou, Hua, Atchison, Kevin, Warwick, Helen K., Atkinson, Peter J., Jefferson, Julius, Xu, Lin, Aschmies, Suzan +10 more·2008·The Journal of Neuroscience
DOI 10.1523/jneurosci.1972-08.2008PMC PMC6671315
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Abstract

Inheritance of the apoE4 allele (ε4) increases the risk of developing Alzheimer's disease; however, the mechanisms underlying this association remain elusive. Recent data suggest that inheritance of ε4 may lead to reduced apoE protein levels in the CNS. We therefore examined apoE protein levels in the brains, CSF and plasma of ε2/2, ε3/3, and ε4/4 targeted replacement mice. These apoE mice showed a genotype-dependent decrease in apoE levels; ε2/2 >ε3/3 >ε4/4. Next, we sought to examine the relative contributions of apoE4 and apoE3 in the ε3/4 mouse brains. ApoE4 represented 30–40% of the total apoE. Moreover, the absolute amount of apoE3 per allele was similar between ε3/3 and ε3/4 mice, implying that the reduced levels of total apoE in ε3/4 mice can be explained by the reduction in apoE4 levels. In culture medium from ε3/4 human astrocytoma or ε3/3, ε4/4 and ε3/4 primary astrocytes, apoE4 levels were consistently lower than apoE3. Secreted cholesterol levels were also lower from ε4/4 astrocytes. Pulse-chase experiments showed an enhanced degradation and reduced half-life of newly synthesized apoE4 compared with apoE3. Together, these data suggest that astrocytes preferentially degrade apoE4, leading to reduced apoE4 secretion and ultimately to reduced brain apoE levels. Moreover, the genotype-dependent decrease in CNS apoE levels, mirror the relative risk of developing AD, and suggest that low levels of total apoE exhibited by ε4 carriers may directly contribute to the disease progression, perhaps by reducing the capacity of apoE to promote synaptic repair and/or Aβ clearance.

AI snapshot

Written from the paper’s full text.

TL;DR

ApoE4 targeted replacement mice and apoE4-expressing astrocytes show lower apoE levels than apoE2 or apoE3, largely because newly synthesized apoE4 is degraded faster and secreted less. The authors propose that this genotype-dependent reduction in CNS apoE may contribute to Alzheimer’s disease risk by limiting apoE-mediated synaptic repair and/or Aβ clearance.

Key findings

  • In 20-week-old apoE targeted replacement mice, brain apoE levels decreased by genotype: ε2/2 > ε3/3 > ε4/4. Relative to ε2/2, cortical apoE was reduced by 24.0 ± 4.1% in ε3/3 and 39.4 ± 3.3% in ε4/4; hippocampal apoE was reduced by 12.0 ± 3.9% and 26.2 ± 3.8%, respectively. ApoE mRNA did not differ significantly across genotypes, suggesting a post-translational mechanism.
  • In ε3/4 mice, apoE4 represented only 30–40% of total apoE across brain, CSF, and plasma, rather than the expected ~50%. The absolute amount of apoE3 per allele was similar between ε3/3 and ε3/4 mice, implying that reduced total apoE in ε3/4 mice is explained by reduced apoE4.
  • In primary astrocytes, ε4/4 cultures secreted 28 ± 8.4% less apoE than ε3/3 cultures, and apoE4 was only 31.1 ± 1.8% of total apoE in ε3/4 astrocytes. Secreted cholesterol was also lower: ε3/4 showed an 18.2 ± 6.2% decrease and ε4/4 a 52.0 ± 10.7% decrease relative to ε3/3.
  • Pulse-chase experiments showed enhanced apoE4 degradation: cell-associated apoE4 half-life was 49 min versus 96 min for apoE3; after a 120 min chase, 43.1 ± 4.4% of apoE4 was degraded versus 21.6 ± 7.9% of apoE3. At 300 min, 18.9 ± 2.5% of apoE4 was secreted versus 27.8 ± 2.7% of apoE3, while 51.7 ± 4.0% versus 41.0 ± 4.1% was degraded.

Methods

  • Male ε2/2, ε3/3, ε3/4, and ε4/4 targeted replacement mice (12–20 weeks old) were used; plasma, CSF, frontal cortex, and hippocampus were collected. ApoE was measured by total apoE and apoE4-selective Meso Scale Discovery immunoassays, Western blotting, and quantitative RT-PCR.
  • Human astrocytoma cell lines CCF-STTG1 (ε3/4) and U118 (ε2/4), plus primary astrocytes from ε3/3, ε3/4, and ε4/4 mice, were cultured. ApoE-containing lipoproteins were isolated by flotation ultracentrifugation, and cholesterol was measured with the Amplex Red assay; TO901317 was used to induce apoE expression.
  • Pulse-chase experiments used [35S]methionine labeling in primary astrocytes, followed by apoE immunoprecipitation, SDS-PAGE, and phosphorimaging. Statistical analysis used one-way or two-way ANOVA with post tests, unpaired t tests, and nonlinear regression for half-life.

Limitations

  • The paper states that CSF apoE differences between ε3/3 and ε4/4 did not reach statistical significance because of high within-genotype variability. It also states that it cannot rule out accumulation of apoE fragments in disease states, since only healthy young animals were examined.
  • Evident from the text: the main in vivo findings come from mouse targeted replacement models, not human brain tissue, and the in vitro work uses astrocytoma lines and primary mouse astrocytes. The study examines young animals without Alzheimer’s disease pathology, so it cannot directly establish that low apoE4 levels cause disease progression.
  • Evident from the text: some apoE4 measurements were limited by assay sensitivity, requiring lipoprotein isolation, concentration, or LXR agonist induction; cell-associated apoE4 could not be accurately detected in CCF-STTG1 lysates.

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

Integrity signals

Registry

Crossref · 10.1523/jneurosci.1972-08.2008

Cites

69 of 69 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

8 of 42 cited sources checked · 3 supported · 1 flagged · accuracy not yet measured

  • Findingcitation

    Newly synthesized astrocytic apoE appears to be present in two distinct pools: a stable pool of cell-associated apoE (~30%) that is neither secreted nor degraded, and a mobile pool (~70%) targeted for either secretion or intracellular degradation.

    “As previously noted for macrophages (Kockx et al., 2004), newly synthesized astrocytic apoE appears to be present in two distinct pools, a stable pool of cell-associated apoE (ϳ30%), that is neither secreted nor degraded over the duration of the experiment, and a mobile pool of apoE (ϳ70%) that is targeted for either secretion or intracellular degradation.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Kockx et al., 2004 source
  • Study design and conductcitation

    Detergent extraction of plasma, CSF, and brain samples before quantification precluded well-known issues of apolipoprotein detection in aqueous solutions.

    “We also detergent extracted plasma, CSF and brain samples before quantification, thus precluding well known issues of apolipoprotein detection in aqueous solutions (Krul and Cole, 1996;Ramaswamy et al., 2005).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Krul and Cole, 1996 source
    • cites Ramaswamy et al., 2005 source
  • Premisecitation

    ApoE4 carriers have increased Aβ burden.

    “apoE4 carriers have increased A␤ burden (Beffert et al., 1999;Corder et al., 2004;Fryer et al., 2005).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Beffert et al., 1999 source
    • cites Corder et al., 2004 source
    • cites Fryer et al., 2005 source

      The Discussion reports greater Aβ deposition in cerebral vessels of apoE4-expressing mice than apoE3-expressing mice, supporting increased burden in that model. It also says human APOE4 is associated with more cerebral amyloid angiopathy in patients with AD, but that parenchymal Aβ was independent of APOE genotype. The source therefore does not establish a general increase in Aβ burden among human apoE4 carriers. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Premisecitation

    In humans and animal models, apoE genotype is correlated with apoE protein levels in plasma, with ε2 showing the highest protein levels and ε4 the lowest.

    “In humans and animal models, apoE genotype is correlated with apoE protein levels in plasma, with ␧2 showing the highest protein levels and ␧4 the lowest (Eto et al., 1986;Gregg et al., 1986;Raffai et al., 2001) (Fig. 2).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Eto et al., 1986 source
    • cites Gregg et al., 1986 source

      The Abstract (p. 1) reports lower plasma apoE concentration in a human apoE4 homozygote than in apoE3 homozygotes, and the Discussion (p. 5) notes similarly low levels in three other apoE4 individuals. The paper does not establish that apoE2 has the highest plasma protein level or report plasma-level comparisons in animal models. (LLM, conf=0.89)

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

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

  • Interpretationcitation

    Preferential degradation of apoE4 relative to apoE3 in astrocytes leads to a reduced capacity for delivery of cholesterol to neurons for repair.

    “the preferential degradation of apoE4 relative to apoE3 in astrocytes leads to a reduced capacity for the delivery of cholesterol the neurons for repair”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Ramaswamy et al., 2005 source

      The astrocyte-culture results (page not provided) show less apoE4 than apoE3 in conditioned medium. The Discussion (page not provided) proposes degradation of apoE4 in astrocytes as a possibility, not an established cause. The paper does not report reduced cholesterol delivery to neurons for repair, so the claimed consequence is unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • May combine two claims. 19
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Premisecitation

    LXR agonists increase murine CNS apoE levels and decrease Aβ levels in APP transgenic mice.

    “dosing of APP transgenic mice with LXR agonists, which increase murine CNS apoE levels, also decrease A␤ levels (Koldamova et al., 2005;Burns et al., 2006;Riddell et al., 2007).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Koldamova et al., 2005 source

      The in vivo results report reduced soluble Aβ40 and Aβ42 in T0901317-treated APP23 mice (Fig. 7). But the in vivo APP23 results (Fig. 6D) and Discussion explicitly report no significant change in brain apoE protein after treatment, contrary to the claimed increase in murine CNS apoE. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites Burns et al., 2006 source
    • cites Riddell et al., 2007 source

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

    Premisecitation

    Engineering an apoE4-like Arg-61 domain interaction into murine apoE affects CNS apoE biology and leads to low brain levels of apoE.

    “Recently, Ramaswamy et al. (2005) published data to suggest that engineering an apoE4-like, Arg-61 domain interaction into murine apoE also affects CNS apoE biology and leads to low brain levels of apoE.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Ramaswamy et al. (2005) source

  • May combine two claims.

    Study design and conductcitation

    A detergent-rich lysis buffer has been shown to inhibit apoE oligomerization and fully release lipid-bound apoE epitopes that, if not exposed, may hamper accurate detection of apoE levels by immunoassay.

    “Such a detergent-rich lysis buffer has been shown to inhibit apoE oligomerization and fully release the lipid-bound apoE epitopes which, if not exposed, may hamper accurate detection of apoE levels by immunoassay (Krul and Cole, 1996;Ramaswamy et al., 2005).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Krul and Cole, 1996 source
    • cites Ramaswamy et al., 2005 source

      The Discussion says detergents remove bound lipid, making apoE epitopes available to antibodies, and that unexposed epitopes can affect immunoassay results. It separately says denaturing conditions prevent oligomerization; it does not establish that the detergent-rich lysis buffer alone does so. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    ε3/3 mice showed a 24.0 ± 4.1% and ε4/4 mice showed a 39.4 ± 3.3% decrease in total cortical apoE relative to ε2/2.

    “with ␧3/3 showing a 24.0 Ϯ 4.1% and ␧4/4 showing a 39.4 Ϯ 3.3% decrease in total cortical apoE relative to ␧2/2”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the hippocampus, ε3/3 had a 12.0 ± 3.9% and ε4/4 had a 26.2 ± 3.8% reduction in apoE relative to ε2/2.

    “whereas in the hippocampus ␧3/3 had a 12.0 Ϯ 3.9% and ␧4/4 a 26.2 Ϯ 3.8% reduction relative to ␧2/2.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Low levels of both 22 and 10 kDa fragments were detected in pulse-chase experiments; these fragments degraded at the same rate as full-length apoE and did not accumulate in ε3/3 or ε4/4 cells.

    “Although a low level of both 22 and 10 kDa fragments were detected in the pulse-chase experiments, these fragments degraded at the same rate as full-length apoE and did not accumulate in either ␧3/3 or ␧4/4 cells (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CSF apoE levels show a genotype-dependent decrease (ε2/2 3.5 ± 0.6, ε3/3 1.5 ± 0.3, ε4/4 1.1 ± 0.3 g/ml), but the difference between ε3/3 and ε4/4 did not reach statistical significance.

    “Finally, we measured CSF levels of apoE across all three genotypes and again observed a genotype-dependent decrease in apoE levels (␧2/2, 3.5 Ϯ 0.6 vs ␧3/3, 1.5 Ϯ 0.3 vs ␧4/4, 1.1 Ϯ 0.3 g/ml); however, because of the high degree of variability in CSF apoE levels within each genotype, the differences between ␧3/3 and ␧4/4 did not reach statistical significance (Fig. 2e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Treating CCF-STTG1 cells with heparinase increased the total amount of both apoE3 and apoE4 secreted over 24 h, but did not significantly alter the ratio of apoE4 to apoE3.

    “Moreover, treating CCF-STTG1 cells with heparinase to release the cell surface bound apoE (Hara et al. 2003) increased the total amount of both apoE3 and apoE4 secreted into the media over a 24 h period, but it did not significantly alter the ratio of apoE4 to apoE3 (supplemental Fig. S1, available at www.jneurosci.org as supplemental material).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hara et al. 2003 source

  • May combine two claims.

    Findingown data

    Cholesterol secreted into the medium showed a genotype-dependent decrease, ε3/3 > ε3/4 > ε4/4, with ε3/4 showing an 18.2 ± 6.2% and ε4/4 showing a 52.0 ± 10.7% decrease relative to ε3/3.

    “Finally, there was a genotype-dependent decrease in cholesterol secreted into the medium, ␧3/3 Ͼ␧3/4 Ͼ␧4/4 (n ϭ 3-9 per group, p Ͻ 0.001; one-way ANOVA), with ␧3/4 showing a 18.2 Ϯ 6.2% and ␧4/4 showing a 52.0 Ϯ 10.7% decrease in cholesterol relative to ␧3/3.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At the 120 min time point, the mobile pool of apoE4 appears completely exhausted, whereas apoE3 cells still have capacity in their mobile pool for either secretion or degradation.

    “It is of note that at the 120 min time point, the mobile pool of apoE4 appears to be completely exhausted, whereas apoE3 cells still have capacity in their mobile pool for either secretion or degradation (Fig. 6a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CCF-STTG1 genotyped as ε3/4 and U118 genotyped as ε2/4.

    “we subsequently identified two astrocytomas that expressed the apoE4 isoform; CCF-STTG1 genotyped as ␧3/4 and U118 genotyped as ␧2/4 (Fig. 4a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In frontal cortex and hippocampus, the absolute amount of apoE3 per allele is similar between ε3/3 and ε3/4 mice, as is the amount of apoE4 per allele in ε4/4 and ε3/4 mice.

    “Moreover, in frontal cortex and hippocampus, the absolute amount of apoE3 per allele is similar between ␧3/3 and ␧3/4 mice, as is the amount of apoE4 per allele in ␧4/4 and ␧3/4 mice (Fig. 3c,d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At the end of the 300 min chase, 27.8 ± 2.7% of newly synthesized apoE3 was secreted and 41.0 ± 4.1% was degraded, compared with 18.9 ± 2.5% of apoE4 secreted and 51.7 ± 4.0% degraded.

    “Ultimately, at the end of the 300 min chase period, 27.8 Ϯ 2.7% of newly synthesized apoE3 has been secreted into the media and 41.0 Ϯ 4.1% has been degraded, compared with 18.9 Ϯ 2.5% of apoE4 being secreted and 51.7 Ϯ 4.0% degraded (Fig. 6d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Astrocytic apoE4 shows enhanced degradation and reduced secretion relative to apoE3.

    “Astrocytic apoE4 shows enhanced degradation and reduced secretion relative to apoE3.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The apoE4 allele accounts for between 50 and 60% of the genetic variation in Alzheimer's disease.

    “The association of allele four of apoE (␧4) as a genetic risk factor for Alzheimer's disease (AD) has been well established, accounting for between 50 -60% of the genetic variation in the disease (Corder et al., 1993;Raber et al., 2004).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Corder et al., 1993 source
    • cites Raber et al., 2004 source

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

    Premisecitation

    ApoE in the brain is derived from local synthesis with little contribution from the periphery.

    “ApoE in the brain is derived from local synthesis with little contribution from the periphery (Ferna ´ndez-Miranda et al., 1997).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ferna ´ndez-Miranda et al., 1997

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

  • May combine two claims.

    Premisecitation

    In plasma, apoE4 preferentially binds to large, triglyceride-rich, very low-density lipoproteins and is more rapidly catabolized by the liver, leading to low steady-state plasma levels.

    “In plasma, apoE4 preferentially binds to large, triglyceride-rich, very low-density lipoproteins and is more rapidly catabolized by the liver, thus leading to low steady state plasma levels.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Raffai et al., 2001

      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).

    Premisecitation

    Stabilization of a molten globule state caused by point mutations in the CFTR gene targets the protein for enhanced degradation.

    “the stabilization of a molten globule state caused by point mutations in the cystic fibrosis transmembrane conductance regulator gene is known to target this protein for enhanced degradation (Santucci et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Santucci et al., 2008 source

  • May combine two claims.

    Interpretationown data

    Together, the data suggest that astrocytes preferentially degrade apoE4, leading to reduced apoE4 secretion and ultimately to reduced brain apoE levels.

    “Together, these data suggest that astrocytes preferentially degrade apoE4, leading to reduced apoE4 secretion and ultimately to reduced brain apoE levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Preferential degradation of apoE4 in astrocytes leads to reduced apoE protein levels and cholesterol secretion.

    “leading to a reduced level of apoE protein and cholesterol secretion”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Anti-α-tubulin was used as a loading control for brain homogenates.

    “Anti-␣-tubulin (Upstate) was used as a loading control for brain homogenates.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Primary astrocyte cultures contained approximately 90% glial fibrillary acidic protein-positive astrocytes.

    “Remaining adherent cells, containing ϳ90% glial fibrillary acidic protein-positive astrocytes, were plated 48 h before experiments.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    ApoE knockout brain homogenates were used as a negative control for the assay.

    “ApoE knockout brain homogenates were used as a negative control for this assay.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The total apoE assay recognized all forms of apoE equally well, whereas the apoE4 assay selectively detected purified apoE4 and apoE4 from brain lysates of homozygous ε4/4 targeted replacement mice.

    “The total apoE assay recognized all forms of apoE equally well (Fig. 1b), whereas the apoE4 assay selectively detected purified apoE4 (Fig. 1c) and apoE4 from brain lysates of homozygous ␧4/4 targeted replacement mice (Fig. 1d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ApoE4 is the least stable of all apoE isoforms, denaturing at lower concentrations of urea and at lower temperatures.

    “it is known from in vitro observations that apoE4 is the least stable of all the apoE isoforms: apoE4 denatures at lower concentrations of urea and at lower temperatures”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Morrow et al., 2002 source
25 of 25

  • The paper relies on this without support.

    ApoE-targeted replacement mice are a valid model for human apoE metabolism and brain apoE levels.

    “Together, our data show that the human ␧4 allele is preferentially degraded in astrocytes, leading to a reduced level of apoE protein and cholesterol secretion and low steady state brain and CSF levels of apoE in transgenic animals.”

  • The paper relies on this without support.

    Human astrocytoma cell lines (CCF-STTG1, U118) are representative of primary human astrocytes.

    “we observed a consistent decrease in the level of apoE4 secreted into the media of primary astrocytes and human astrocytomas.”
2 of 2

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?

  • Astrocytes and microglia are the main ApoE-producers in the brain.

    “astrocytes and microglia are the main ApoE‐producers in the brain [64]”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [64]

    The Introduction states that brain ApoE is produced by astrocytes, and the Results document ApoE secretion from primary astrocytes. The passages from our copy do not establish that microglia produce ApoE or that astrocytes and microglia together are its main producers in the brain. Page numbers were not available in the indexed passages. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • U87-SphK2 cells were established based on the human astrocytoma U87 cell line, which has the most common ApoE genotype, ε3/ε3.

    “we established SphK2 stably overexpressing cells based on human astrocytoma U87 cell line (U87-SphK2 cells), which have the most common genotype of ApoE, ε3/ε3 (26).”

    From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [26]

    The astrocytoma cell-culture methods identify U87 as a human astrocytoma cell line, and the Results say the authors genotyped human astrocytoma lines. Our copy does not state that U87 has the ε3/ε3 genotype or that it is the most common ApoE genotype. Establishing U87-SphK2 cells is the citing authors’ own work, not a finding attributed to this source. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • APOE2 expression leads to increased APOE levels in mouse models and human brain, which can influence amyloid pathology.

    “It has also been shown that APOE2 expression leads to increased APOE levels in mouse models and human brain (Riddell et al, 2008; Bales et al, 2009; Conejero-Goldberg et al, 2014), which can influence amyloid pathology.”

    From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Riddell et al, 2008

    The Figure 2 caption (indexed under Discussion; page unavailable) reports genotype-dependent apoE levels in the brains of targeted-replacement mice, including ε2/2 mice. The Discussion proposes that brain apoE levels may affect amyloid-β clearance and deposition. The paper does not demonstrate increased apoE levels in human brain with APOE2 expression, nor directly test the effect of APOE2 on amyloid pathology. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • A recent in vitro study has shown that apoE4 is degraded more quickly than apoE2 or apoE3 in primary mouse astrocyte cultures.

    “Interestingly, a recent in vitro study has shown that apoE4 is degraded more quickly than apoE2 or apoE3 in primary mouse astrocyte cultures (Riddell et al., 2008).”

    From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Riddell et al., 2008

    The Results and Figure 6 report faster degradation of apoE4 than apoE3 in primary mouse astrocyte cultures (page not specified in our copy). They do not report an apoE2 degradation comparison, so the claim’s apoE2 component is unsupported. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Cholesterol release is reduced in primary glial cultures from apoE-TR mice expressing apoE4 compared with glial cells expressing apoE3.

    “cholesterol release is reduced in primary glial cultures from apoE-TR mice expressing apoE4 compared with glial cells expressing apoE3 (35,73).”

    From APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease (2012) · cites this paper as [35]

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.

  • Pulse-labeling concentration differs between methods and Figure 6

    Minor

    The pulse-chase methods specify 250 Ci/ml [ 35 S]methionine, while the Figure 6 caption specifies 200 Ci/ml for the experiment.

  • Figure 6 calls homozygous mice heterozygous

    Minor

    The Figure 6 caption describes apoE3/3 and apoE4/4 mice as heterozygous, whereas the pulse-chase methods describe the same genotypes as homozygous.

2 of 2

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Related

Authors
Riddell, D. R., Zhou, H., Atchison, K., Warwick, H. K., Atkinson, P. J., Jefferson, J., Xu, L., Aschmies, S., Kirksey, Y., Hu, Y., Wagner, E., Parratt, A., Xu, J., Li, Z., Zaleska, M. M., Jacobsen, J. S., Pangalos, M. N., & Reinhart, P. H.
Affiliations
Wyeth
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2008-11-05
Volume
28
Issue
45
Pages
11445-11453
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.1972-08.2008
PMC
PMC6671315
OpenAlex
W2088526201
Cited by
342
References
68
Citations by year
2026: 11 · 2025: 17 · 2024: 27 · 2023: 23 · 2022: 29 · 2021: 17 · 2020: 16 · 2019: 20 · 2018: 9 · 2017: 14 · 2016: 24 · 2015: 14 · 2014: 22 · 2013: 19 · 2012: 21
FWCI
11.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
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, APOE ε4, APOE3, APOE polymorphism, Alzheimer's disease, astrocytes, apoE secretion, cholesterol secretion, targeted replacement mice, amyloid-beta clearance
MeSH terms
Benzenesulfonamides, Analysis of Variance, Animals, Animals, Newborn, Apolipoproteins E, Brain, Cells, Cultured, DNA Mutational Analysis, Dose-Response Relationship, Drug, Fluorocarbons, Humans, Hydrocarbons, Fluorinated, Male, Mice, Transgenic, Neuroglia, Polymorphism, Genetic, RNA, Messenger, Sulfonamides, Time Factors, Culture Media, Conditioned, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-31.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-31.

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.

What counts as a claim ›How we measure confidence ›How we check this ›

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