The DOI matches its Crossref record; 69 of the 69 references it cites were found in a registry or an index; 11 of the 42 sources its claims cite were checked for support.
Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels
Open accessAbstract
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.
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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.
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Claims the paper makes
38 Own result · 16 Own interpretation · 8 No full text of the sources · 7 Own method · 6 Partly supported · 4 Sources not found · 3 Supported · 2 Not checked yet · 1 Supported so far · 1 Not supported · 1 No basis given · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“the denaturation pattern of apoE4 suggests that it can exist as a partially folded intermediate or a molten globule state (Morrow et al., 2002).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Discussion
What the sources say
- Supportedcites Morrow et al., 2002 source
The Results report that plateaus in the apoE4 denaturation curves at pH 4.0 suggest a stable folding intermediate. The Discussion says structural characterization of that intermediate is consistent with a molten globule. The paper identifies the tested material as the 22-kDa amino-terminal domain of apoE4. (LLM, conf=0.93)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Results
What the sources say
- Supportedcites Kockx et al., 2004 source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
hedged- Asserted: passes — The authors put it forward as true.
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- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Discussion
What the sources say
- Not checked — no full text of the sourcecites Krul and Cole, 1996 source
- Supportedcites Ramaswamy et al., 2005 source
The citation supports the rationale for the citing authors’ method, not a claim that Ramaswamy et al. detergent-extracted all three sample types. In the Discussion, Ramaswamy et al. explain that lipid binding can interfere with apoE extraction and immunodetection, including in soluble fractions, and that detergent treatment makes apoE epitopes available to antibodies. They also describe detergent use in plasma apoE assays. (LLM, conf=0.90)
boosteddirect- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“endogenous CNS-derived apoE-containing lipoprotein particles bind to A and promote its clearance and degradation (DeMattos et al., 2004;Koistinaho et al., 2004;Manelli et al., 2004;Stratman et al., 2005;Trommer et al., 2005)”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Discussion
What the sources say
- Partly supportedcites DeMattos et al., 2004 sourceExperimental — accuracy not yet measured
The passage labeled Abstract (page unavailable) says apoE may bind extracellular Aβ and facilitate local clearance of apoE/Aβ complexes. It does not establish that CNS-derived apoE-containing lipoprotein particles promote Aβ degradation. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites Koistinaho et al., 2004 source
- Not checked — no full text of the sourcecites Manelli et al., 2004 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“apoE4 carriers have increased A burden (Beffert et al., 1999;Corder et al., 2004;Fryer et al., 2005).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Discussion
What the sources say
- Not checked — no full text of the sourcecites Beffert et al., 1999 source
- Not checked — no full text of the sourcecites Corder et al., 2004 source
- Partly supportedcites Fryer et al., 2005 sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Discussion
What the sources say
- Not checked — no full text of the sourcecites Eto et al., 1986 source
- Partly supportedcites Gregg et al., 1986 sourceExperimental — accuracy not yet measured
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)
- Not matchedcites Raffai et al., 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the preferential degradation of apoE4 relative to apoE3 in astrocytes leads to a reduced capacity for the delivery of cholesterol the neurons for repair”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Discussion
What the sources say
- Partly supportedcites Ramaswamy et al., 2005 sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, these mice showed a genotype-dependent decrease in cortical and hippocampal apoE levels, 2/2 Ͼ3/3 Ͼ4/4 (cortex, p Ͻ 0.0001; hippocampus, p Ͻ 0.0001, one-way ANOVA) (Fig. 2a)”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Results
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, our data show that the human 4 allele is preferentially degraded in astrocytes”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Astrocytes from 4/4 mice secreted 28 Ϯ 8.4% less apoE into the culture medium than 3/3 cultures (n ϭ 6, p Ͻ 0.05).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- It may state two separate claims as one. 19
- Probably not a substantial claim. 7
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“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).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Discussion
What the sources say
- Disputedcites Koldamova et al., 2005 sourceExperimental — accuracy not yet measured
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.
- Not checked — no full text of the sourcecites Burns et al., 2006 source
- Not checked — no full text of the sourcecites Riddell et al., 2007 source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Disputed
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Introduction
What the sources say
- Supportedcites Ramaswamy et al. (2005) source
The Introduction describes gene targeting that replaced the mouse apoE threonine codon with arginine to model apoE4 domain interaction. The Results section, “Lower brain levels of Arg-61 apoE than wild-type apoE,” reports lower Arg-61 apoE levels in the hemibrain and several brain regions; the Discussion identifies domain interaction as a major contributing factor. (LLM, conf=0.94)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Animals.
What the sources say
- Not checked — no full text of the sourcecites Krul and Cole, 1996 source
- Partly supportedcites Ramaswamy et al., 2005 sourceExperimental — accuracy not yet measured
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)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Discussion
What the sources say
- Partly supportedcites Morrow et al., 2002 sourceExperimental — accuracy not yet measured
The Results report that apoE4’s 22-kDa amino-terminal fragment denatures at a lower urea concentration than apoE3’s, and that apoE2 is most resistant to unfolding in urea. The paper does not report a lower thermal-denaturation temperature for apoE4; its Abstract instead says the apoE4 amino-terminal domain is less susceptible to thermal denaturation than the other isoforms. The experiments also concern fragments rather than whole apoE proteins. (LLM, conf=0.86)
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Results
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Results
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Results
What the sources say
- Not checked — no full text of the sourcecites Hara et al. 2003 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, there was a genotype-dependent decrease in cholesterol secreted into the medium, 3/3 Ͼ3/4 Ͼ4/4 (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.”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Results
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Results
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we subsequently identified two astrocytomas that expressed the apoE4 isoform; CCF-STTG1 genotyped as 3/4 and U118 genotyped as 2/4 (Fig. 4a).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Astrocytic apoE4 shows enhanced degradation and reduced secretion relative to apoE3.”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Introduction
What the sources say
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“ApoE in the brain is derived from local synthesis with little contribution from the periphery (Ferna ´ndez-Miranda et al., 1997).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Introduction
What the sources say
- Not matchedcites Ferna ´ndez-Miranda et al., 1997
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“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.”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Discussion
What the sources say
- Not matchedcites Raffai et al., 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“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).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Discussion
What the sources say
- Not checked — no full text of the sourcecites Santucci et al., 2008 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these data suggest that astrocytes preferentially degrade apoE4, leading to reduced apoE4 secretion and ultimately to reduced brain apoE levels.”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“leading to a reduced level of apoE protein and cholesterol secretion”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Anti-␣-tubulin (Upstate) was used as a loading control for brain homogenates.”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Animals.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Remaining adherent cells, containing ϳ90% glial fibrillary acidic protein-positive astrocytes, were plated 48 h before experiments.”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Animals.
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“ApoE knockout brain homogenates were used as a negative control for this assay.”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Animals.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“astrocytes and microglia are the main ApoE‐producers in the brain [64]”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: APOE3 Christchurch homozygote glioprotection (2023) · cites this paper as [64]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“Although there are some conflicting studies (61), several groups have reported that the concentration of apoE in the brains of human apoE knock-in mice varies in an apoE isoform-dependent manner, that is, E2>E3>E4 (14, 62, 63).”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [63]
The cited source says what the claim attributes to it.
In the citing paper
“Notably, astrocytes are the major producers of cerebral ApoE [64], which has been reported to play a relevant role in Aβ clearance [63].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: APOE3 Christchurch homozygote glioprotection (2023) · cites this paper as [64]
The cited source says what the claim attributes to it.
In the citing paper
“The advantage of using N2a cells was that the transfected cells expressed comparable human ApoE, which enabled the comparisons of the three ApoE isoforms in parallel and precluded compounding complexity resulting from the differences in ApoE expression levels as reported in the hApoE-TR mice (Riddell et al., 2008;Sullivan et al., 2011).”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Riddell et al., 2008
The cited source says what the claim attributes to it.
In the citing paper
“ApoE4 in particular is associated to decreased total levels of ApoE [34]”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [34]
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Pulse-chase experiments and metabolic labeling of cell proteins with [ 35 S]-methionine.
“incubated in methionine-free DMEM with 250 Ci/ml [ 35 S]methionine for 3 h.”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Discussion
“incubated in methionine-free DMEM with 200 Ci/ml [ 35 S]methionine for 3 h.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Discussion
“Primary astrocytes from apoE3/3 and apoE4/4 heterozygous mice were cultured 24 h in serum-free media”
§ Neurobiology of Disease Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels > Pulse-chase experiments and metabolic labeling of cell proteins with [ 35 S]-methionine.
“Primary astrocytes were prepared from 3/3 and 4/4 homozygous mice”
Citations
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BackgroundApolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides
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Isoform-specific proteolysis of apolipoprotein-E in the brain
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“We did find differences in CNS ApoE2 and ApoE4 FSR and monoexponential FCR (p,0.05, n = 2, Table S2) in ApoE2/E4 individuals; however, this trend was not reproduced in the FTR (compartmental modeling).”
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Apolipoprotein C-I is an APOE genotype-dependent suppressor of glial activation
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A Multifaceted Role for apoE in the Clearance of Beta-Amyloid across the Blood-Brain Barrier
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APOEgenotype-dependent modulation of astrocyte chemokine CCL3 production
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A multi‐hit hypothesis for an APOE4 ‐dependent pathophysiological state
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Function and Comorbidities of Apolipoprotein E in Alzheimer′s Disease
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Cellular senescence and the blood–brain barrier: Implications for aging and age-related diseases
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Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice
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Apolipoprotein E Genotype e2: Neuroprotection and Its Limits
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The Role of Apolipoprotein E Isoforms in Alzheimer’s Disease
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Metadata
- 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 (US)
- 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
- PMC
- PMC6671315
- OpenAlex
- W2088526201
- Cited by
- 346
- References
- 68
- Citations by year
- 2026: 13 · 2025: 14 · 2024: 27 · 2023: 23 · 2022: 27 · 2021: 17 · 2020: 17 · 2019: 21 · 2018: 11 · 2017: 14 · 2016: 24 · 2015: 15 · 2014: 24 · 2013: 19 · 2012: 22
- FWCI
- 7.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- 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
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