Apolipoprotein E, Especially Apolipoprotein E4, Increases the Oligomerization of Amyloid β Peptide
Open accessAbstract
Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder causing dementia. Massive deposition of amyloid β peptide (Aβ) as senile plaques in the brain is the pathological hallmark of AD, but oligomeric, soluble forms of Aβ have been implicated as the synaptotoxic component. The apolipoprotein E ε 4 (apoE ε4) allele is known to be a genetic risk factor for developing AD. However, it is still unknown how apoE impacts the process of Aβ oligomerization. Here, we found that the level of Aβ oligomers in APOE ε4/ε4 AD patient brains is 2.7 times higher than those in APOE ε3/ε3 AD patient brains, matched for total plaque burden, suggesting that apoE4 impacts the metabolism of Aβ oligomers. To test this hypothesis, we examined the effect of apoE on Aβ oligomer formation. Using both synthetic Aβ and a split-luciferase method for monitoring Aβ oligomers, we observed that apoE increased the level of Aβ oligomers in an isoform-dependent manner (E2 < E3 < E4). This effect appears to be dependent on the ApoE C-terminal domain. Moreover, these results were confirmed using endogenous apoE isolated from the TBS-soluble fraction of human brain, which increased the formation of Aβ oligomers. Together, these data show that lipidated apoE, especially apoE4, increases Aβ oligomers in the brain. Higher levels of Aβ oligomers in the brains of APOE ε4/ε4 carriers compared with APOE ε3/ε3 carriers may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD.
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- Findingown data
The level of TBS-soluble amyloid beta peptide oligomers in APOE epsilon 4/epsilon 4 AD patient brains is significantly higher than in APOE epsilon 3/epsilon 3 AD patient brains.
“Taken together, the level of TBS-soluble Aβ oligomers in APOEε4/ε4 AD patient brains was significantly higher than that in APOEε3/ε3 AD patient brains.”
Quote in the paperSubstantial claim- Rests on an assumption: The low-molecular-weight amyloid beta peptide likely reflects dimers and trimers.
- Findingown data
Immunoprecipitation of apoE with two separate polyclonal antibodies pulled down amyloid beta peptide from these fractions.
“Immunoprecipitation of apoE using each of two separate polyclonal antibodies (anti-apoE Ig (Calbiochem) and anti-apoE Ig (Millipore)) pulled down Aβ from these fractions (Figure 2C).”
Quote in the paperSubstantial claim - Findingown data
There is no correlation between amyloid plaque burden and TBS-soluble amyloid beta peptide levels (r = -0.01, P = 0.95).
“We compared the amount of total soluble Aβ with the histochemically defined amounts of amyloid deposited in senile plaques, and found no correlation between plaque burden and levels of soluble Aβ (Figure 1D, r=−0.01, P=0.95).”
Quote in the paperSubstantial claim - Findingown data
High-molecular-weight amyloid beta peptide and apoE are detected in similar fractions from 185 kDa to 256 kDa in the TBS-soluble fraction from an APOE epsilon 3/epsilon 3 AD brain.
“We also detected HMW Aβ and apoE in similar fractions from 185 kDa to 256 kDa using SEC-separated samples from the TBS-soluble fraction of an APOEε3/ε3 AD patient brain.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE is secreted in high-density lipoprotein particles in the brain.
- Findingown data
In size-exclusion chromatography of TBS-soluble fraction from an APOE epsilon 4/epsilon 4 AD brain, amyloid beta peptide elutes in high-molecular-weight fractions from 94 kDa to 217 kDa and in low-molecular-weight fractions from 8.6 kDa to 16 kDa.
“We found that fractions eluting from 94 kDa to 217 kDa strongly exhibited 4 kDa Aβ (hereafter called high-molecular weight (HMW) Aβ) and fractions eluting from 8.6 kDa to 16 kDa also exhibited 4 kDa Aβ (hereafter low-molecular weight (LMW) Aβ).”
Quote in the paperSubstantial claim- Rests on an assumption: The 4 kDa band corresponds to monomeric amyloid beta peptide under the denaturing conditions used.
- Rests on an assumption: The 8 kDa band corresponds to SDS-stable amyloid beta peptide dimers.
- Findingown data
TBS-soluble amyloid beta peptide levels in APOE epsilon 4/epsilon 4 AD brains are 6.9 times higher than in APOE epsilon 2/epsilon x AD brains.
“6.9 times higher than that in APOEε2/εx AD patient brains”
Quote in the paperSubstantial claim - Findingown data
The TBS-soluble fraction from APOE epsilon 4/epsilon 4 AD brains has substantially higher amounts of amyloid beta peptide in every size-exclusion chromatography peak compared with APOE epsilon 3/epsilon 3 AD brains.
“Remarkably, we found that the TBS-soluble fraction from APOEε4/ε4 AD patient brains exhibited substantially higher amounts of Aβ in every peak compared to APOEε3/ε3 AD patient brains.”
Quote in the paperSubstantial claim - Findingown data
ApoE concentration in the TBS-soluble fraction is similar among control and AD cases regardless of APOE genotype.
“We measured the concentration of apoE in TBS-soluble fraction from the brains of control and AD cases by specific ELISA and found that it is similar among control and AD cases regardless of genotypes (Figure 1E).”
Quote in the paperNot a substantial claim - Findingown data
In size-exclusion chromatography followed by ELISA of TBS-soluble fractions from APOE epsilon 3/epsilon 3 and APOE epsilon 4/epsilon 4 AD brains, amyloid beta peptide elutes in high-molecular-weight fractions from 100 kDa to 200 kDa, around 90 kDa, around 30 kDa, and in low-molecular-weight fractions from 6 kDa to 20 kDa.
“we found that Aβ eluted into fractions from 100 kDa to 200 kDa as HMW Aβ, fractions around 90 kDa, fractions around 30 kDa and fractions from 6 kDa to 20 kDa (the latter LMW Aβ, likely reflecting Aβ dimers and Aβ trimers.”
Quote in the paperSubstantial claim- Rests on an assumption: The low-molecular-weight amyloid beta peptide likely reflects dimers and trimers.
- Findingown data
Amyloid beta peptide and apoE elute in identical size-exclusion chromatography fractions from 185 kDa to 256 kDa in the TBS-soluble fraction from an APOE epsilon 4/epsilon 4 AD brain.
“We found that Aβ and apoE eluted in identical fractions, ranging from 185 kDa to 256 kDa, suggesting that HMW Aβ may interact with apoE on the HDL particles.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE is secreted in high-density lipoprotein particles in the brain.
- Findingown data
In the absence of apoE, amyloid beta peptide trimers and tetramers disappeared within 6 hours and were replaced by smear bands after 6 hours.
“In the absence of apoE, the Aβ trimers and Aβ tetramers disappeared within 6 hours and were replaced by smear bands after 6 hours (Figure 3A, PBS panel).”
Quote in the paperSubstantial claim - Findingown data
In AD patient brains matched for total plaque burden, the level of TBS-soluble amyloid beta peptide is 2.7 times higher in APOE epsilon 4/epsilon 4 brains than in APOE epsilon 3/epsilon 3 brains.
“Despite the AD groups being matched for amyloid plaque burden (Figure 1C), the level of TBS-soluble Aβ in APOEε4/ε4 AD patient brains was 2.7 times higher than that in APOEε3/ε3 AD patient brains”
- Also stated in: § Abstract · plain
“the level of Aβ oligomers in APOEε4/ε4 AD patient brains is 2.7 times higher than those in APOEε3/ε3 AD patient brains, matched for total plaque burden”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
ApoE 192-242 luminescence was lower than that of apoE 192-272.
“ApoE 192-242 luminescence was even lower than that of apoE 192-272”
Quote in the paperSubstantial claim - Findingown data
ApoE CTF significantly enhanced luminescence to a similar extent as full-length apoE3.
“whereas apoE CTF significantly enhanced the luminescence to a similar extent as full-length apoE3”
Quote in the paperSubstantial claim - Findingown data
ApoE eluted in fraction 8 from AD and control brain by immunoblotting.
“We also found that apoE eluted in fraction 8 from AD and control brain by immunoblotting using a goat anti-apoE antibody”
Quote in the paperSubstantial claim - Findingown data
ApoA-II did not change luminescence from baseline.
“whereas apoA-II did not change the luminescence from baseline”
Quote in the paperNot a substantial claim - Findingown data
The effect of apoE on amyloid beta peptide oligomerization appears to depend on the apoE carboxy-terminal domain.
“This effect appears to be dependent on the ApoE carboxy-terminal domain.”
Quote in the paperSubstantial claim - Findingown data
All four fractions, especially fraction 8 from both AD and control brains, increased luminescence.
“We observed that all four fractions, but especially fraction 8 from both AD and control brains, increased the luminescence”
Quote in the paperSubstantial claim - Findingown data
Purified lipidated apoE dose-dependently enhanced the level of amyloid beta peptide oligomers in an isoform-dependent manner (apoE2 < apoE3 < apoE4).
“We found that purified lipidated apoE dose-dependently enhanced the level of Aβ oligomers in an isoform dependent manner (apoE2 < apoE3 < apoE4).”
Quote in the paperSubstantial claim - Findingown data
ApoE 192-272 did not increase luminescence as strongly as apoE CTF.
“whereas apoE 192-272 did not increase the luminescence as strongly as apoE CTF.”
Quote in the paperSubstantial claim - Findingown data
ApoE 231-299 and apoE 243-299 increased luminescence to the same level as apoE CTF.
“We found that apoE 231-299 and apoE 243-299 increased the luminescence to the same level as apoE CTF”
Quote in the paperSubstantial claim - Findingown data
There was no difference in the levels of apoE in the conditioned media.
“We did not see any difference in the levels of apoE in the conditioned media (Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
Endogenous apoE isolated from the TBS-soluble fraction of human brain increased the formation of amyloid beta peptide oligomers.
“Moreover, these results were confirmed using endogenous apoE isolated from the TBS-soluble fraction of human brain, which increased the formation of Aβ oligomers.”
Quote in the paperSubstantial claim - Findingown data
ApoA-II did not change luminescence compared with GFP transfection (91.8 ± 5.1% for apoA-II).
“On the other hand, apoA-II, one of the other apolipoproteins in brain HDL particles, did not change the luminescence compared to GFP transfection (91.8 ± 5.1 % in apoA-II, 200.3 ± 10.2 % in apoE2, 275.5 ± 15.0 % in apoE3, 338.1 ± 18.5 % in apoE4, p<0.05 (E2 vs E3; E3 vs E4)).”
Quote in the paperNot a substantial claim - Findingown data
Lipidated apoE2, apoE3, and apoE4 support the generation of oligomeric Aβ to different extents.
“These data suggest that lipidated apoE2, 3 or 4 supportsoligomeric Aβ generation to different extents”
Quote in the paperSubstantial claim - Findingown data
Transient overexpression of apoE2, apoE3, or apoE4 in HEK293 cells increased Aβ oligomers through apoE's carboxy-terminal domain in an isoform-dependent manner (apoE2 < apoE3 < apoE4).
“Second, transient overexpression of apoE2, apoE3 or apoE4 in HEK293 cells stably expressing split-luciferase tagged Aβ oligomers increased Aβ oligomers through apoE’s carboxy-terminal domain in an isoform dependent manner (apoE2 < apoE3 < apoE4)”
Quote in the paperSubstantial claim - Findingown data
No significant shift in the elution profile of Aβ oligomers was observed with apoEs.
“We observed no significant shift in the elution profile of Aβ oligomers by apoEs.”
Quote in the paperNot a substantial claim - Findingown data
In the presence of lipidated apoE2, apoE3, or apoE4, amyloid beta peptide trimers and tetramers gradually accumulated during incubation.
“In contrast, in the presence of lipidated apoE2, apoE3 or apoE4, the bands for Aβ trimers and Aβ tetramers gradually accumulated during the incubation period (Figure 3A, apoE2, apoE3, apoE4 panels).”
Quote in the paperSubstantial claim - Findingown data
Fractions from APOEε4/ε4 AD patients led to significantly increased Aβ oligomer levels compared with fractions from APOEε3/ε3 AD patients.
“We observed that fractions from APOEε4/ε4 AD patients led to significantly increased levels of Aβ oligomers compared to that from APOEε3/ε3 AD patients”
Quote in the paperSubstantial claim - Findingown data
Lipidated apoE4 significantly increased the level of amyloid beta peptide trimers and tetramers compared with samples incubated without apoE (130.0 ± 19.0% for trimers and 235.3 ± 85.4% for tetramers).
“Lipidated apoE4 significantly increased the level of Aβ trimers and tetramers compared to the sample incubated without apoE (130.0 ± 19.0% in trimers and 235.3 ± 85.4% in tetramers)”
Quote in the paperSubstantial claim - Findingown data
Aβ and apoE co-eluted into high-molecular-weight fractions in SEC-separated interstitial fluid from APPPS mouse brains.
“We confirmed that Aβ and apoE co-eluted into HMW fractions in SEC-separated interstitial fluid from APPPS mouse brains using a microdialysis techniques with a 1,000 kDa molecular weight cut-off membrane probe”
Quote in the paperSubstantial claim - Findingown data
ApoE2, apoE3, or apoE4 each increased luminescence in conditioned media of doubly expressing HEK293 cells.
“We found that apoE2, apoE3 or apoE4 each increased the luminescence.”
Quote in the paperSubstantial claim - Findingown data
ApoE on HDL particles from immortalized astrocytes expressing human apoE2, apoE3, or apoE4 promoted oligomerization of synthetic Aβ, split-luciferase tagged Aβ oligomers, or low-molecular-weight Aβ from AD brains.
“First, apoE on HDL particles, purified from conditioned media of immortalized astrocytes expressing human apoE2, apoE3 or apoE4 promoted the oligomerization of synthetic Aβ, split-luciferase tagged Aβ oligomers or LMW Aβ isolated from TBS-soluble fraction of AD patients’ brains Aβ (Figure 3).”
Quote in the paperSubstantial claim - Findingown data
Lipidated apoE2 and apoE3 did not significantly increase the level of amyloid beta peptide oligomers.
“On the other hand, lipidated apoE2 and apoE3 did not exhibit significant increase of the level of the Aβ oligomers (Figure 3B).”
Quote in the paperSubstantial claim - Findingown data
ApoE-immunodepleted samples significantly decreased luminescence compared with immunodepletion using a control antibody.
“We found that apoE-immunodepleted sample significantly decreased the level of luminescence compared to immunodepletion using a control antibody”
Quote in the paperSubstantial claim - Findingown data
Incubation of amyloid beta peptide with apoE3 or apoE4 yielded higher levels of trimers and tetramers than incubation with apoE2.
“qualitative inspection of the gels show that incubation of Aβ with apoE3 or apoE4 yielded higher levels of Aβ trimers and Aβ tetramers than incubation with apoE2.”
Quote in the paperSubstantial claim - Findingown data
ApoE3 Δ243-299 significantly decreased luminescence compared with apoE3 Δ273-299.
“and that apoE3 Δ243-299 significantly decreased the luminescence compared to apoE3 Δ273-299”
Quote in the paperSubstantial claim - Findingown data
ApoE2, apoE3, and apoE4 did not enhance luminescence within cell lysates (100.0 ± 12.7% for apoA-II, 89.9 ± 9.7% for apoE2, 96.4 ± 13.9% for apoE3, 92.5 ± 2.2% for apoE4, no significant difference).
“We found that apoE2, apoE3 and apoE4 did not enhance the luminescence within cell lysates (100.0 ± 12.7 % in apoA-II, 89.9 ± 9.7 % in apoE2, 96.4 ± 13.9 % in apoE3, 92.5 ± 2.2 % in apoE4, no significant difference).”
Quote in the paperSubstantial claim - Findingown data
No significant correlation was observed between plaque burden and levels of TBS-soluble Aβ oligomers.
“No significant correlation was observed between plaque burden and levels of TBS-soluble Aβ oligomers (r=−0.01, p=0.95, Spearman’s rank correlation test)”
Quote in the paperSubstantial claim - Findingown data
Treatment with 8 M guanidine-HCl increases the measured concentration of Aβ in high-molecular-weight Aβ fractions under the specific ELISA conditions used.
“and the treatment with 8 M Guanidine-HCl increases the measured concentration of Aβ in HMW Aβ fractions using our specific ELISA conditions (Figure 2A).”
Quote in the paperSubstantial claim - Findingown data
High-molecular-weight Aβ from TBS-soluble fractions is under-estimated in ELISA experiments due to a possible masking effect by itself or interacting molecules.
“In this study we observed that the level of HMW Aβ from TBS-soluble fraction is under-estimated in ELISA experiments due to a possible masking effect either by itself or interacting molecules”
Quote in the paperSubstantial claim - Findingown data
Lipidated apoE4 increased the level of synthetic Aβ trimers and tetramers.
“we found lipidated apoE4 increased the level of synthetic Aβ trimers and tetramers (Figure 3B)”
Quote in the paperSubstantial claim - Findingown data
ApoE4 enhanced the ratio of high-molecular-weight Aβ oligomers compared with apoE2 or apoE3.
“We also found that apoE4 enhanced the ratio of HMW Aβ oligomers compared to apoE2 or apoE3”
Quote in the paperSubstantial claim - Findingown data
ApoA-I only slightly increased the levels of Aβ oligomers.
“We observed that apoA-I only slightly increased the levels of Aβ oligomers (Figure 5).”
Quote in the paperNot a substantial claim - Findingown data
ApoE increased Aβ oligomerization in an isoform-dependent manner (apoE2 < apoE3 < apoE4).
“Using both synthetic Aβ (Figure 3A) and a split-luciferase complementation assay (Figure 3C and Figure 4), we found that apoE increased Aβ oligomerization in an isoform dependent manner (apoE2 < apoE3 < apoE4).”
Quote in the paperSubstantial claim - Premisecitation
Having two APOE epsilon 4 alleles is associated with more than a tenfold increased risk of Alzheimer's disease compared with the APOE epsilon 3/epsilon 3 genotype.
“Inheritance of two copies of the APOEε4 allele is associated with a >10-fold increased risk for developing AD compared to the most common APOEε3/ε3 genotype (Corder et al., 1993; Strittmatter et al., 1993a).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Corder et al., 1993
Not checked in the free run.
- cites Strittmatter et al., 1993a
Not checked in the free run.
- Premisecitation
Soluble oligomeric forms of amyloid beta peptide are important for synaptic dysfunction, cognitive impairment, and neurodegeneration.
“Recent data, however, suggest that instead of, or in addition to, plaques, soluble oligomeric forms of Aβ are crucial for synaptic dysfunction, cognitive impairment and neurodegeneration (Lesné et al., 2006; Shankar et al., 2008; Koffie et al., 2009; Wu et al., 2010).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Lesné et al., 2006
Not checked in the free run.
- cites Shankar et al., 2008
Not checked in the free run.
- cites Koffie et al., 2009
Not checked in the free run.
- Interpretationown data
The amount of TBS-soluble amyloid beta peptide is independent of the amount of deposited amyloid plaques.
“This suggests that the amount of TBS-soluble Aβ is independent of the amount of deposited amyloid plaques.”
Quote in the paperSubstantial claim - Interpretationown data
The increase in amyloid beta peptide ELISA signal after guanidine treatment is consistent with epitopes being masked in the high-molecular-weight fraction.
“consistent with the idea that epitopes were masked in the HMW fraction.”
Quote in the paperSubstantial claim - Interpretationown data
ApoE interacts with amyloid beta peptide oligomers in human AD brain.
“These data suggest that apoE interacts with Aβ oligomers in human AD brain and thus may impact their oligomerization in the brain.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE is secreted in high-density lipoprotein particles in the brain.
- Interpretationreasoning
Lipidation of apoE may be crucial for enhancing Aβ oligomerization.
“thus the lipidation of apoE may be crucial in the enhancement of Aβ oligomerization”
Quote in the paperSubstantial claim - Study design and conductown data
The AD groups were matched for amyloid plaque burden (3.7 ± 1.4% in APOE epsilon 2/epsilon x, 3.0 ± 1.3% in APOE epsilon 3/epsilon 3, and 3.4 ± 2.1% in APOE epsilon 4/epsilon 4, with no significant difference).
“we carefully selected brains to have equal amyloid load in an adjacent cortical region by an immunohistochemical analysis using anti-Aβ antibody 10D5 (3.7 ± 1.4 % in APOEε2/εx AD patients, 3.0 ± 1.3 % in APOEε3/ε3 AD patients and 3.4 ± 2.1 % in APOEε4/ε4 AD patients, no significant difference) (Figure 1C).”
Quote in the paperSubstantial claim - Interpretationown data
Endogenous apoE from human brain increased the level of Aβ oligomers.
“These data indicate that endogenous apoE from human brain increased the level of Aβ oligomers”
Quote in the paperSubstantial claim - Interpretationown data
ApoE, especially apoE4, appears to enhance Aβ oligomers.
“ApoE, especially apoE4, appears to enhance Aβ oligomers.”
Quote in the paperSubstantial claim - Interpretationown data
ApoE influences amyloid beta peptide oligomers only in the extracellular compartment.
“suggesting that apoE influences Aβ oligomers only in the extracellular compartment.”
Quote in the paperSubstantial claim - Interpretationown data
ApoE enhanced the level of amyloid beta peptide oligomers in an isoform-dependent manner (apoE2 < apoE3 < apoE4).
“suggesting that apoE enhanced the level of Aβ oligomers in an isoform dependent manner (apoE2 < apoE3 < apoE4).”
Quote in the paperSubstantial claim - Interpretationown data
Lipidated apoE, especially apoE4, increases amyloid beta peptide oligomers in the brain.
“Taken together, these data show that lipidated apoE, especially apoE4, increases Aβ oligomers in the brain.”
Quote in the paperSubstantial claim - Interpretationown data
ApoE4 may stabilize amyloid beta peptide oligomers.
“suggesting that apoE4 may stabilize the Aβ oligomers.”
Quote in the paperSubstantial claim - Interpretationown data
The amino-terminal fragments of apoE are loss-of-function molecules regarding Aβ oligomerization.
“suggesting that the amino-terminal fragments of apoE is a loss-of-function molecule regarding Aβ oligomerization”
Quote in the paperSubstantial claim - Premisecitation
APOEε4/ε4 AD patients have significantly higher colocalization of apoE and Aβ oligomers at synapses compared with APOEε3/ε3 AD patients.
“Recently we found that apoE colocalized with Aβ oligomers at synapse in the brain of AD patient brains using an array tomographic technique and found that APOEε4/ε4 AD patients have significantly higher level of colocalization of apoE and Aβ oligomers at synapse compared to APOEε3/ε3 AD patients (Koffie et al., 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Koffie et al., 2012
Not checked in the free run.
- Study design and conductown data
Similar expression levels of the apoE mutants were confirmed by immunoblotting.
“We confirmed similar expression levels of these apoE mutants by immunoblotting using mAb 6C5 and mAb 3H1.”
Quote in the paperSubstantial claim - Interpretationown data
ApoE4 impacts the metabolism of amyloid beta peptide oligomers.
“suggesting that apoE4 impacts the metabolism of Aβ oligomers.”
Quote in the paperSubstantial claim - Interpretationown data
ApoA-I and apoJ/clusterin may also modulate the metabolism of Aβ oligomers in the brain.
“This suggests that apoA-I and apoJ/clusterin may also modulate the metabolism of Aβ oligomers in the brain”
Quote in the paperSubstantial claim- Rests on an assumption: ApoA-I, apoA-II, and apoJ/clusterin are present on HDL particles in the brain.
- Interpretationown data
Lipidated particles supported by several apolipoproteins may act as a scaffold for Aβ interactions.
“reinforces the idea that lipidated particles supported by several apolipoproteins may act as a scaffold for Aβ interactions.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoA-I, apoA-II, and apoJ/clusterin are present on HDL particles in the brain.
- Interpretationown data
The tertiary structure of apoE is relevant to the apoE isoform-dependent effect on Aβ oligomerization.
“suggesting that the tertiary structure of apoE is relevant to the apoE isoform-dependent effect on Aβ oligomerization”
Quote in the paperSubstantial claim - Study design and conductcitation
The split-luciferase complementation assay monitors amyloid beta peptide oligomers specifically and quantitatively without background from monomers.
“This technique has the advantage of monitoring Aβ oligomers specifically and quantitatively without background from monomers.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hashimoto et al., 2011
Not checked in the free run.
- Study design and conductown data
There was no difference in apoE expression levels among apoE3, apoE4, and apoE4 R61T.
“We did not see any difference in the levels of apoE expression among apoE3, apoE4 and ApoE4 R61T.”
Quote in the paperSubstantial claim - Interpretationown data
Residues 243-299 in the carboxy-terminal region of apoE are especially important for enhancing Aβ oligomers.
“Taken together, these data suggest that the 243-299 amino acid residues in the carboxy-terminal region of apoE are especially important in the enhancement of Aβ oligomers.”
Quote in the paperSubstantial claim - Interpretationreasoning
Lipidated apoE derived from human brain also enhances Aβ oligomerization.
“supporting the hypothesis that lipidated apoE derived from human brain also enhances Aβ oligomerization.”
Quote in the paperSubstantial claim - Study design and conductown data
Similar expression levels of the apoE fragments were confirmed by immunoblotting.
“We confirmed similar expression levels of these apoE fragments by immunoblotting using a goat anti-apoE polyclonal antibody and mAb 3H1.”
Quote in the paperSubstantial claim - Interpretationown data
The carboxy-terminal region of apoE, especially a domain within residues 243-272, is essential for apoE's support of Aβ oligomers.
“Taken together, these results strongly argue that the carboxy-terminal region of apoE, especially a domain within amino-acid residues 243-272, is essential for apoE’s support of Aβ oligomers.”
Quote in the paperSubstantial claim - Interpretationown data
There is a possibility of an in vivo interaction between Aβ and apoE.
“suggesting the possibility of an in vivo interaction between them.”
Quote in the paperSubstantial claim - Interpretationown data
These observations plausibly help explain the major risk for AD associated with APOEε4 inheritance.
“it is plausible that these observations help explain the major risk for AD associated with APOEε4 inheritance.”
Quote in the paperSubstantial claim- Rests on an assumption: APOEε4 inheritance is a major risk factor for Alzheimer's disease.
- Study design and conductnone given
The AD groups were matched for deposited amyloid burden.
“Importantly, these AD groups were matched for deposited amyloid burden.”
Quote in the paperSubstantial claim - Interpretationreasoning
ApoE interacts with Aβ oligomers through its carboxy-terminal region.
“In summary, we provide in vivo and in vitro evidence that apoE interacts with Aβ oligomers through its carboxy-terminal region”
Quote in the paperSubstantial claim - Interpretationreasoning
Not only full-length apoE4 but also carboxy-terminal fragments containing residues 243-272 may additionally enhance Aβ oligomer formation in APOEε4/ε4 brains.
“Taken together, these results argue that not only full-length apoE4 but also carboxy-terminal fragments of apoE4 containing the region at 243-272 amino-acid residues may additionally enhance the formation of Aβ oligomers in APOEε4/ε4 brains.”
Quote in the paperSubstantial claim - Premisecitation
Higher levels of apoE carboxy-terminal fragments were observed in APOEε4/ε4 AD brains compared with APOEε3/ε3 AD brains.
“In a recent study using the anti-apoE mAb 3H1 that recognizes the amino acids 243-272, we observed significantly higher levels of apoE carboxy-terminal fragments in APOEε4/ε4 AD brains compared to APOEε3/ε3 AD brains.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Jones et al., 2011
Not checked in the free run.
- Premisecitation
Aβ is closer to the apoE carboxy-terminal region than to its amino-terminal region within doubly-labeled senile plaques.
“using in situ FLIM-FRET in human AD brain specimens, we found that Aβ is closer to the apoE carboxy-terminal region than to its amino-terminal region within doubly-labeled senile plaques (Jones et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Jones et al., 2011
Not checked in the free run.
- Interpretationown data
The 2.7-fold difference in TBS-soluble Aβ oligomers between APOEε4/ε4 and APOEε3/ε3 groups cannot be attributed to disruption of senile plaques during homogenization.
“so that the 2.7-fold difference in the levels of TBS-soluble Aβ oligomers between them cannot be attributed to the disruption of a higher amount of senile plaques in the APOEε4/ε4 group during the homogenization of the specimens.”
Quote in the paperSubstantial claim - Premisecitation
Crossing apoA-I-deficient mice with APP transgenic mice did not alter Aβ deposition in the brain.
“By contrast, crossing apoA-I-deficient mice with APP transgenic mice did not alter Aβ deposition in the brain (Fagan et al., 2004)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Fagan et al., 2004 source
Not checked in the free run.
- Interpretationown data
The amino-terminal domain might be important for modulating Aβ oligomerization.
“suggesting that amino-terminal domain might be important to modulate Aβ oligomerization.”
Quote in the paperSubstantial claim - Interpretationreasoning
ApoJ/clusterin may modify Aβ oligomer formation in the human brain similarly to apoE.
“suggesting that apoJ/clusterin may modify Aβ oligomer formation in the human brain similarly to apoE.”
Quote in the paperNot a substantial claim- Rests on an assumption: ApoA-I, apoA-II, and apoJ/clusterin are present on HDL particles in the brain.
- May combine two claims. 32
- Classified as probably not a substantial claim. 18
May combine two claims.
Findingown dataIn ELISA of size-exclusion chromatography fractions, the measured concentration of amyloid beta peptide in high-molecular-weight fractions dramatically increased after guanidine-HCl treatment, while low-molecular-weight fractions showed no difference.
“We found that the measured concentration of Aβ in HMW fractions dramatically increased, while the levels of Aβ in LMW fractions exhibited no difference (Figure 2A)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataEndogenous apoE extracted from TBS-soluble fractions of human AD and control brains increased Aβ oligomers, with apoE3 < apoE4.
“Third, endogenous apoE extracted from TBS-soluble fraction of human AD and control brains also increased Aβ oligomers, again apoE3 < apoE4”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataApoE2 NTF, apoE3 NTF, and apoE4 NTF did not enhance luminescence.
“We found that apoE2 NTF, apoE3 NTF or apo4 NTF did not enhance the luminescence”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn TBS-soluble fractions, Aβ oligomer levels are 2.7-fold higher in AD APOEε4/ε4 brains than in APOEε3/ε3 brains and 6.9-fold higher than in APOEε2/εx brains, while non-demented controls have negligible levels.
“In this study, we demonstrate that the levels of Aβ oligomers in TBS-soluble fraction of AD APOEε4/ε4 brains are 2.7-fold higher compared to APOEε3/ε3 patient brains and 6.9-fold higher compared to APOEε2/εx patient brains, whereas brains from non-demented controls had negligible levels of Aβ oligomers”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataApoE4 R61T increased Aβ oligomer levels to the same extent as apoE3 but not as much as apoE4.
“We found that apoE4 R61T increased the level of Aβ oligomers to the same extent as apoE3, but not as high as apoE4”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataApoE3 Δ243-272, apoE3 Δ273-299, and apoE3 Δ243-299 significantly decreased luminescence compared with full-length apoE3.
“We found that apoE3 Δ243-272, apoE3 Δ273-299 and apoE3 Δ243-299 significantly decreased the level of luminescence compared to full-length apoE3”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAβ and apoE co-eluted into high-molecular-weight fractions in SEC-separated TBS-soluble fractions from AD brains and co-immunoprecipitated.
“We also found that Aβ and apoE co-eluted into HMW fractions in SEC-separated TBS-soluble fraction from AD brains, and co-immunoprecipitated”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataApoA-I and apoJ/clusterin enhance luminescence, though to a lesser extent than apoE3.
“Interestingly, apoA-I and apoJ/clusterin also enhance the luminescence, although to a lesser extent than apoE3”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataApoE4 significantly increased the level of high-molecular-weight putative 24-36 mer oligomers and decreased the level of dimers.
“We found that apoE4 significantly increased the level of HMW putative 24~36 mer oligomers (or complexes of Aβ with other proteins) and decreased the level of dimers”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataApoE4 increased luminescence more than apoE2 and apoE3, and apoE3 increased luminescence more than apoE2.
“ApoE4 significantly increased the luminescence to a greater extent than apoE2 and apoE3, and apoE3 significantly increased the luminescence to a greater extent than apoE2”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBoth apoE and high-molecular-weight Aβ oligomers eluted into fractions 7 and 8 from the TBS extract of human brain.
“We separated the TBS-extract of human brain by SEC and found both apoE and HMW Aβ oligomers are eluted into fraction 7 and 8 (Figure 2B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAfter incubation with purified lipidated apoE, about 6.5% of low-molecular-weight amyloid beta peptide elutes in the high-molecular-weight fraction, compared with 0.5% without apoE, an increase of over 10-fold.
“about 6.5% of LMW Aβ instead elutes in the HMW Aβ fraction (Figure 3D, 6.5 ± 0.3% with apoE, 0.5 ± 0.7 without apoE), an increase of over 10-fold.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataApoJ/clusterin and apoA-I increased the level of Aβ oligomers.
“In addition to apoE, we found apoJ/clusterin and apoA-I, other apolipoproteins on the HDL particles, increased the level of Aβ oligomers (Figure 5).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationApoE interacts with amyloid beta peptide in vitro and in vivo in cerebrospinal fluid and brain.
“Previous studies have revealed that apoE interacts with Aβ in vitro (Strittmatter et al., 1993b; LaDu et al., 1994) and in vivo, both in the cerebrospinal fluid (Strittmatter et al., 1993a) and in the brain (Näslund et al., 1995).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Strittmatter et al., 1993b
Not checked in the free run.
- cites LaDu et al., 1994 source
Not checked in the free run.
- cites Strittmatter et al., 1993a
Not checked in the free run.
May combine two claims.
PremisecitationIn APP transgenic mice expressing apoE2, apoE3, and apoE4, apoE4 significantly slows amyloid beta peptide clearance relative to E2 and E3 but does not affect amyloid beta peptide synthesis.
“in APP transgenic mice expressing apoE2, E3, and E4, apoE4 significantly slows Aβ clearance relative to E2 and E3 but has no effect on Aβ synthesis (Castellano et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Castellano et al., 2011
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationApolipoprotein E is a known amyloid beta peptide binding protein and a genetic risk factor for Alzheimer's disease.
“Apolipoprotein E (apoE) is a known Aβ binding protein and is a genetic risk factor for AD (Bu et al., 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bu et al., 2009
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown dataOligomerization was assessed using two preparations, synthetic Aβ and a quantitative split-luciferase assay, with confirmatory results.
“Similarly, we assessed oligomerization using two preparations: synthetic Aβ and a quantitative split-luciferase assay, with confirmatory results.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationApoE has a receptor-binding domain in its amino-terminal region and a lipid-binding domain in its carboxy-terminal region.
“ApoE has a receptor-binding domain in the amino-terminal region and a lipid-binding domain in the carboxy-terminal region (Figure 6A, Chou et al., 2005).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chou et al., 2005
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationSplit-luciferase tagged Aβ oligomers consist of high-molecular-weight 24-36 mers and low-molecular-weight dimers by SEC analysis.
“We previously demonstrated that the split-luciferase tagged Aβ oligomers consist of high-molecular weight (HMW) 24~36 mer and low-molecular weight dimers by SEC analyses (Hashimoto et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hashimoto et al., 2011
Not checked in the free run.
May combine two claims.
Interpretationown dataThe apoE and Aβ high-molecular-weight complex endogenously exists in the brain and is not a product of mechanical homogenization.
“suggesting that the apoE and Aβ HMW complex endogenously exists in the brain and is not a product caused during the mechanical homogenization steps.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationIn an in vitro amyloid beta peptide fibrillization assay, apoE inhibits fibrillization especially in the seeding phase.
“In an in vitro Aβ fibrillization assay, apoE is known to inhibit Aβ fibrillization especially in the seeding phase of Aβ fibrillization (Evans et al., 1995; Naiki et al., 1997).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Evans et al., 1995
Not checked in the free run.
- cites Naiki et al., 1997
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationSenile plaque density in APOE epsilon 4/epsilon 4 carrier AD patients is on average significantly higher than in APOE epsilon 3/epsilon 3 carrier AD patients.
“Because it is known that the level of senile plaque density in APOEε4/ε4 carrier AD is on average significantly higher than that in APOEε3/ε3 carrier AD (Rebeck et al 1993)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Rebeck et al 1993
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationThe current view of AD pathophysiology emphasizes deleterious effects of Aβ oligomers on synapses, leading to synaptic dysfunction and progressive memory impairment.
“The current view of AD pathophysiology emphasizes the deleterious effects of Aβ oigomers on synapses, leading to synaptic dysfunction, and progressive memory impairment in AD patients (Lesné et al., 2006; Shankar et al., 2008; Li et al., 2009; Wu et al., 2010).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Lesné et al., 2006
Not checked in the free run.
- cites Shankar et al., 2008
Not checked in the free run.
- cites Li et al., 2009
Not checked in the free run.
May combine two claims.
Interpretationown dataLipidated apoE enhanced the oligomerization of amyloid beta peptide or stabilized amyloid beta peptide oligomers.
“This result may suggest that lipidated apoE enhanced the oligomerization of Aβ or stabilized the Aβ oligomers.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHEK293 cells transfected with human apoE3 and apoE4 naturally secrete apoE lipoparticles into culture media.
“Although HEK293 cells transfected with human apoE3 and apoE4 naturally secrete apoE lipoparticles into the culture media (LaDu et al., 2006)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites LaDu et al., 2006
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe genotype data were not revealed during subsequent biochemical assays.
“these data were not revealed during subsequent biochemical assays.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationApoE2 and apoE3 preferentially adopt an open conformation, while apoE4 preferentially adopts a closed conformation.
“ApoE2 and apoE3 prefer an open-conformation, whereas apoE4 prefers a closed-conformation due to a difference at amino acid residue 112 between apoE4 (Arg) and apoE2, E3 (Cys) (Dong et al., 1994; Mahley et al., 2009)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Dong et al., 1994 source
Not checked in the free run.
- cites Mahley et al., 2009
Not checked in the free run.
May combine two claims.
PremisecitationThe residue 112 difference indirectly changes a salt bridge and alters the domain-domain interactions between the amino and carboxyl halves of apoE.
“indirectly this changes a salt bridge and alters the domain-domain interactions of the amino and carboxyl halves of apoE.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Dong et al., 1994 source
Not checked in the free run.
- cites Mahley et al., 2009
Not checked in the free run.
May combine two claims.
Interpretationown dataApoE, especially apoE4, impacts amyloid beta peptide oligomer levels by enhancing their formation and stabilizing them once formed.
“These data suggest that apoE, especially apoE4, impacts Aβ oligomer levels by enhancing their formation and stabilizing them once formed.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThe 243-272 region may act to help catalyze oligomer formation.
“as this region may act to help catalyze oligomer formation.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown dataExpression of the apoE fragments was confirmed by immunoblotting with anti-human apoE antibodies.
“In immunoblotting, we confirmed the expression of these apoE fragments using anti-human apoE antibodies.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe carboxy-terminal region of apoE is necessary and sufficient to induce Aβ oligomerization.
“This suggests that the carboxy-terminal region of apoE is necessary and sufficient to induce Aβ oligomerization.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataSelected brains had similar age at death, gender ratio, disease duration, and postmortem interval.
“Selected brains also had a similar age at death, gender ratio, disease duration and similar postmortem interval (Table 1).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataLipidated apoE enhances amyloid beta peptide oligomerization and inhibits further aggregation in vitro.
“These qualitative and quantitative data suggest that lipidated apoE enhances Aβ oligomerization and inhibited further aggregation in vitro.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationThe carboxy-terminal domain of apoE contains the major lipid-binding region at residues 243-272.
“The carboxy-terminal domain of apoE contains the major lipid-binding region (243-272 amino acid residues) (Hatters et al., 2006; Mahley et al., 2009).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Hatters et al., 2006
Not checked in the free run.
- cites Mahley et al., 2009
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationThe immortalized astrocyte cells secrete human apoE in HDL-like particles into conditioned media.
“These immortalized astrocyte cells are known to secrete human apoE’s in HDL-like particles into conditioned media (Morikawa et al., 2005).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Morikawa et al., 2005
Not checked in the free run.
May combine two claims.
InterpretationreasoningApoE4 increases the level of Aβ oligomers in the brain, leading to increased synaptic localization with Aβ oligomers, synaptic dysfunction, and hastening of cognitive impairments.
“Our results suggest that apoE4 increases the level of Aβ oligomers in the brain, leading to increased synaptic localization with Aβ oligomers, synaptic dysfunction and hastening the development of cognitive impairments.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
InterpretationreasoningApoE lipidation may be critical for facilitating Aβ oligomer formation.
“supporting the idea that apoE lipidation may be critical to facilitate Aβ oligomer formation.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationApoJ/clusterin deficient mice crossed with APP transgenic mice exhibit significantly fewer fibrillar Aβ deposits in the brain compared with APP transgenic mice.
“apoJ/clusterin deficient mice crossed with APP transgenic mice exhibit significantly fewer fibrillar Aβ deposits in the brain compared to APP transgenic mice (DeMattos et al., 2002)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites DeMattos et al., 2002
Not checked in the free run.
May combine two claims.
Interpretationown dataLipidated apoE, especially apoE4, might stabilize Aβ oligomers and inhibit their dissociation or further aggregation.
“suggesting that lipidated apoE, especially apoE4 might stabilize Aβ oligomers and inhibit the dissociation or further aggregation of Aβ.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationSoluble oligomeric Aβ in frontal cortex of young adults is higher than in elderly people or Alzheimer's disease patients by ELISA.
“Recently it was reported that the level of soluble oligomeric Aβ in frontal cortex of young adults is higher than that of elderly people or Alzheimer’ disease patients using ELISA experiments (Halmond et al., 2010)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Halmond et al., 2010
Not checked in the free run.
May combine two claims.
InterpretationcitationApoA-I has a small or no effect on Aβ oligomerization and fibrillization.
“indicating a small or no effect of apoA-I on Aβ oligomerization and fibrillization.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCommon variants in the apoJ/clusterin gene CLU have been linked to increased risk of developing AD.
“Common variants in the apoJ/clusterin gene (CLU) have recently been linked to an increased risk of developing AD (Harold et al., 2009; Lambert et al., 2009)”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Harold et al., 2009
Not checked in the free run.
- cites Lambert et al., 2009
Not checked in the free run.
May combine two claims.
Interpretationown dataApoE influences both plaque burden and levels of TBS-soluble Aβ oligomers in an isoform-differential manner.
“Thus, these results indicate that apoE influences both plaque burden and also the levels of TBS-soluble Aβ oligomers in an isoform-differential manner.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe carboxy-terminal domain of apoE is necessary and sufficient to drive Aβ oligomerization, suggesting that apoE may directly interact with Aβ oligomers through its carboxy-terminal region.
“Interestingly, experiments using deletion mutants of apoE demonstrate that the carboxy-terminal domain of apoE is necessary and sufficient to drive Aβ oligomerization, suggesting that apoE may directly interact with Aβ oligomers through its carboxy-terminal region”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataApoE, particularly apoE4, promotes and stabilizes Aβ oligomerization.
“and that apoE, particularly apoE4, promotes and stabilizes Aβ oligomerization.”
Quote in the paperSubstantial claim
The paper relies on this without support.
It is still unknown what factors influence the kinetics of formation of soluble amyloid beta peptide oligomers.
“However, it is still unknown what factors influence the kinetics of formation of soluble Aβ oligomers.”
The paper relies on this without support.
Whether apoE increases the levels of native amyloid beta peptide oligomers remains unknown.
“However, because of the difficulty in monitoring Aβ oligomers specifically and quantitatively, whether apoE increases the levels of native Aβ oligomers remains unknown.”
The paper relies on this without support.
ApoE is secreted in high-density lipoprotein particles in the brain.
“ApoE is secreted in high-density lipoprotein (HDL) particles in the brain.”
The paper relies on this without support.
The 4 kDa band corresponds to monomeric amyloid beta peptide under the denaturing conditions used.
“a 4 kDa band, corresponding (under these denaturing conditions) to monomeric Aβ”
The paper relies on this without support.
The 8 kDa band corresponds to SDS-stable amyloid beta peptide dimers.
“an 8 kDa band corresponding to SDS-stable Aβ dimers”
The paper relies on this without support.
The low-molecular-weight amyloid beta peptide likely reflects dimers and trimers.
“the latter LMW Aβ, likely reflecting Aβ dimers and Aβ trimers.”
The paper relies on this without support.
ApoA-I, apoA-II, and apoJ/clusterin are present on HDL particles in the brain.
“Besides apoE, apoA-I, apoA-II and apoJ/clusterin are also present on the HDL particles in the brain.”
The paper relies on this without support.
APOEε4 inheritance is a major risk factor for Alzheimer's disease.
“the major risk for AD associated with APOEε4 inheritance.”
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?
In vitro, Aβ42 aggregation was highest with human ApoE3, lower with human ApoE3ch (similar to ApoE2), and lowest with no ApoE.
“Aβ42 aggregation was highest in the presence of human ApoE3 protein (C-terminus domain), lower in the presence of human ApoE3ch (similar to that observed in the presence of ApoE213), and lowest in the absence of any ApoE (Extended Data 3).”
From Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report (2019) · cites this paper as [13]
The Results (page not supplied) report that ApoE increased Aβ oligomerization in vitro, with ApoE3 producing more oligomers than ApoE2; the carboxy-terminal fragment also enhanced oligomerization. The paper does not report an ApoE3ch condition, so it cannot support the claimed comparison between ApoE3ch and ApoE3 or ApoE2. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe literature suggests that there are isoform-dependent differences in ApoE-plaque associations but that several factors, such as ApoE lipidation state, compartment or cell type of origin, and Aβ conformational state, also have important roles in ApoE-Aβ interactions.
“The literature suggests that there are isoform-dependent differences in ApoE–plaque associations but that several factors, such as ApoE lipidation state, compartment or cell type of origin, and Aβ conformational state, also have important roles in ApoE–Aβ interactions52–56.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [56]
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 measuredSeveral recent studies provided evidence to support increased content of Aβ oligomers in the extracellular space in brains of patients with AD expressing human ApoE4 isoform, and intraneuronally in mice expressing human ApoE4 isoform after inhibition of Aβ-degrading enzyme neprilysin.
“Several recent studies provided evidence to support increased content of Ab oligomers in the extracellular space in brains of patients with AD, expressing the human ApoE4 isoform, 37,38 and intraneuronally in mice expressing human ApoE4 isoform after inhibition of Ab-degrading enzyme neprilysin.39”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [37]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThe increased propensity of Aβ to oligomerize in the presence of APOE4 is considered a major mechanism by which APOE4 increases Alzheimer disease risk.
“and the increased propensity of Aβ to oligomerize in the presence of APOE4 is considered a major mechanism by which APOE4 increases AD risk113–116 (Fig. 2c).”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [113]
The Discussion reports that apoE4 promotes and stabilizes Aβ oligomerization, but says it is *plausible* that this helps explain the major AD risk associated with APOEε4. The claim overstates that tentative link by calling oligomerization a major mechanism of increased risk. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAPOE4 is associated with increased oligomerization and deposition of Aβ in vitro and in vivo.
“APOE4 is associated with increased oligomerization and deposition of Aβ in vitro and in vivo113,115,192”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [113]
The Discussion reports in vitro and in vivo evidence that apoE, particularly apoE4, promotes Aβ oligomerization. The Introduction also reports greater fibrillar Aβ deposition with apoE4 in brains and mice. It does not support increased deposition in vitro; the Results instead note that earlier in vitro assays found apoE inhibited Aβ fibrillization. (LLM, conf=0.86)
Experimental — accuracy not yet measured
A split-luciferase complementation assay confirmed that ApoE3ch has a lower ability to trigger Aβ42 aggregation.
“This finding was confirmed using a split-luciferase complementation assay sensitive to the characterization of potentially neurotoxic Aβ42 oligomers13.”
From Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report (2019) · cites this paper as [13]
Experimental — accuracy not yet measuredAβ oligomer levels in APOE4 AD patients' brains are 2.7 times higher than those in APOE3 AD patients.
“This finding also aligns with evidence that Aβ oligomer levels in APOE4 AD patients’ brains are 2.7 times higher than those in APOE3 AD patients [73]”
apoE, especially its apoE4 isoform, facilitates the formation of Aβ oligomers.
“It has been recently appreciated that apoE, especially its apoE4 isoform, facilitates the formation of Aβ oligomers [33,34].”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [33]
Direct interaction between apoE and Aβ facilitates Aβ oligomeric assembly, and all three isoforms promote this process in the rank order E4 > E3 > E2.
“Although it appears that enhanced Aβ oligomerization occurs in settings of elevated Aβx-42 level, which is associated with the apoE4 background, there is experimental evidence to indicate that direct interaction between apoE and Aβ facilitates Aβ oligomeric assembly and that all three isoforms promote this process in the rank order E4 > E3 > E2 [33].”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [33]
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.
ApoE3 is described as both open and closed
MinorThe paper describes apoE3 as preferring an open conformation, then says the R61T mutation makes apoE4 mimic a closed apoE3 conformation. Those descriptions conflict.
“ApoE2 and apoE3 prefer an open-conformation, whereas apoE4 prefers a closed-conformation”
“the apoE4 R61T mutation, which is known to change the apoE4 conformation so that it mimics the closed apoE3 conformation”
Cites
1 retracted
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
Lesné, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., Gallagher, M., & Ashe, K. H. (2006) · Nature · doi:10.1038/nature04533 · Cited by 2,769 · cited 4× · see citing works
“The current view of AD pathophysiology emphasizes the deleterious effects of A oligomers on synapses, leading to synaptic dysfunction, and progressive memory impairment in AD patients (Lesné et al., 2006; Shankar et al., 2008; Li et al., 2009; Wu et al., 2010).”
BackgroundInfluentialRetractedCorder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429 · see citing works
Alzheimer's Disease: Genes, Proteins, and Therapy
Selkoe, D. J. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.741 · Cited by 6,063 · see citing works
Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.5.1977 · Cited by 4,268 · see citing works
Shankar, G. M., Li, S., Mehta, T. H., Garcia-Munoz, A., Shepardson, N. E., Smith, I., Brett, F. M., Farrell, M. A., Rowan, M. J., Lemere, C. A., et al. (2008) · Nature Medicine · doi:10.1038/nm1782 · Cited by 3,685 · see citing works
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Alzheimer’s Disease: The Challenge of the Second Century
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Self-citationStrittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.17.8098 · Cited by 1,363 · see citing works
Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance
Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,227 · cited 1× · see citing works
“Importantly, it has now been shown that in APP-transgenic mice expressing apoE2, E3, and E4, apoE4 significantly slows A clearance relative to E2 and E3 but has no effect on A synthesis (Castellano et al., 2011).”
BackgroundSelf-citationApolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
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Apolipoprotein E in sporadic Alzheimer's disease: Allelic variation and receptor interactions
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Self-citationEarly Aβ accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain
Ingelsson, M., Fukumoto, H., Newell, K. L., Growdon, J. H., Hedley–Whyte, E. T., Frosch, M. P., Albert, M. S., Hyman, B. T., & Irizarry, M. C. (2004) · Neurology · doi:10.1212/01.wnl.0000115115.98960.37 · Cited by 666 · see citing works
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Apolipoprotein E structure: insights into function
Hatters, D. M., Peters-Libeu, C. A., & Weisgraber, K. H. (2006) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.06.008 · Cited by 583 · see citing works
Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS
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Isoform-specific binding of apolipoprotein E to beta-amyloid.
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Self-citationApoE and Clusterin Cooperatively Suppress Aβ Levels and Deposition
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Self-citationProposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes
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Deficiency of ABCA1 Impairs Apolipoprotein E Metabolism in Brain
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Clinical and pathological correlates of apolipoprotein E ε4 in Alzheimer's disease
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Self-citationImpact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels
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Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β
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Alzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta
Griciuc, A., Serrano-Pozo, A., Parrado, A. R., Lesinski, A. N., Asselin, C. N., Mullin, K., Hooli, B., Choi, S. H., Hyman, B. T., & Tanzi, R. E. (2013) · Neuron · doi:10.1016/j.neuron.2013.04.014 · Cited by 1,004 · see citing works
Self-citationAPOE and Alzheimer’s disease: Advances in genetics, pathophysiology, and therapeutic approaches
Serrano-Pozo, A., Das, S., & Hyman, B. T. (2021) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30412-9 · Cited by 1,037 · see citing works
Self-citationThe Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade
Cline, E. N., Bicca, M. A., Viola, K. L., & Klein, W. L. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179941 · Cited by 870 · see citing works
ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756 · see citing works
“The findings of earlier Aβ deposition [87], greater Aβ oligomerization, and lower CSF and plasma Aβ levels in human APOE4 carriers [88, 89] strongly support the idea that apoE isoforms differentially regulate Aβ fibril formation via its interaction with Aβ, and that this interaction may represent a potential target fo…”
BackgroundArboleda-Velasquez, J. F., Lopera, F., O’Hare, M., Delgado-Tirado, S., Marino, C., Chmielewska, N., Saez-Torres, K. L., Amarnani, D., Schultz, A. P., Sperling, R. A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0611-3 · Cited by 598 · see citing works
“…Flp-In™ T-REx™ 293 (Thermo Fisher Scientific) mammalian cells via transient transfection to confirm the impact of these proteins on A β 42 aggregation using a previously published split-luciferase complementation assay 34 and based on the known toxicity of the oligomeric intermediates of A β 35 .”
ApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?
Kanekiyo, T., Xu, H., & Bu, G. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.045 · Cited by 608 · see citing works
Savelieff, M. G., Nam, G., Kang, J., Lee, H. J., Lee, M., & Lim, M. H. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00138 · Cited by 603 · see citing works
ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion
Huang, Y.-W. A., Zhou, B., Wernig, M., & Südhof, T. C. (2017) · Cell · doi:10.1016/j.cell.2016.12.044 · Cited by 528 · see citing works
“ApoE4 enhances Ab oligomerization, suggesting that ApoE4 could predispose to AD by increasing toxic Ab oligomers (Hashimoto et al., 2012).”
Reiman, E. M., Arboleda-Velasquez, J. F., Quiroz, Y. T., Huentelman, M. J., Beach, T. G., Caselli, R. J., Chen, Y., Su, Y., Myers, A. J., Hardy, J., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14279-8 · Cited by 473 · see citing works
Self-citationAlzheimer’s disease: insights into pathology, molecular mechanisms, and therapy
Zheng, Q., & Wang, X. (2024) · Protein & Cell · doi:10.1093/procel/pwae026 · Cited by 454 · see citing works
Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology
Perez-Nievas, B. G., Stein, T. D., Tai, H.-C., Dols-Icardo, O., Scotton, T. C., Barroeta-Espar, I., Fernandez-Carballo, L., de Munain, E. L., Perez, J., Marquie, M., et al. (2013) · Brain · doi:10.1093/brain/awt171 · Cited by 387 · see citing works
“Three different methods were used to detect and quantify soluble amyloid-b species: (i) SDS-PAGE immunoblotting with a mixture of two amyloid-b N-terminal monoclonal antibodies, 82E1 (IBL) and 6E10 (Covance), to increase detection sensitivity (Hashimoto et al., 2012); (ii) two-site sandwich ELISA kit (Wako) that uses…”
MethodSelf-citationApolipoprotein E in Alzheimer's Disease: An Update
Yu, J.-T., Tan, L., & Hardy, J. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014300 · Cited by 394 · see citing works
“…via the blood-brain barrier (BBB) (Bachmeier et al. 2013, (c) Aβ clearance via enzymatic degradation ( Jiang et al. 2008); (d ) Aβ oligomerization (Hashimoto et al. 2012); and (e) Aβ clearance by drainage via the interstitial fluid (Castellano et al. 2011) or perivasculature (Hawkes et al.…”
BackgroundMethodApolipoprotein E, Receptors, and Modulation of Alzheimer’s Disease
Zhao, N., Liu, C.-C., Qiao, W., & Bu, G. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.03.003 · Cited by 370 · see citing works
“7 times higher in AD brains with APOE ε4/4 than those with APOE ε3/3, suggesting that apoE4 impacts the metabolism of Aβ oligomers (38).”
BackgroundBeyond the neuron–cellular interactions early in Alzheimer disease pathogenesis
Henstridge, C. M., Hyman, B. T., & Spires-Jones, T. L. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0113-1 · Cited by 348 · see citing works
Self-citationTolar, M., Abushakra, S., Hey, J. A., Porsteinsson, A., & Sabbagh, M. (2020) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00663-w · Cited by 354 · see citing works
“APOE4 carriers, who are at higher risk of early AD progression and constitute ~ 65% of AD patients, provide an optimal group for clinical efficacy studies and initial approval for drugs targeting neurotoxic soluble Aβ oligomers, since these patients carry a several-fold higher burden of Aβ oligomers compared to noncar…”
Background<i>APOE</i> ε4: The most prevalent yet understudied risk factor for Alzheimer's disease
Michaelson, D. M. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2014.06.015 · Cited by 331 · see citing works
Apolipoprotein E: Structural Insights and Links to Alzheimer Disease Pathogenesis
Chen, Y., Strickland, M. R., Soranno, A., & Holtzman, D. M. (2021) · Neuron · doi:10.1016/j.neuron.2020.10.008 · Cited by 298 · see citing works
“Additionally, soluble Aβ oligomers in the brain were higher in ApoE4 carriers compared to ApoE3 with ApoE2 having the lowest levels (Hashimoto et al., 2012).”
BackgroundSelf-citationMicroglia in Alzheimer Disease: Well-Known Targets and New Opportunities
Hemonnot, A.-L., Hua, J., Ulmann, L., & Hirbec, H. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00233 · Cited by 298 · see citing works
“Thus, APOE-ε4 patients have more Aβ plaques and oligomers than ε3 carriers (Schmechel et al., 1993; Tiraboschi et al., 2004; Hashimoto et al., 2012; Koffie et al., 2012), and mouse models expressing human APOE isoforms mimics the isoform-dependent modifications on Aβ deposits (Fagan et al., 2002;…”
BackgroundAPOE2: protective mechanism and therapeutic implications for Alzheimer’s disease
Li, Z., Shue, F., Zhao, N., Shinohara, M., & Bu, G. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00413-4 · Cited by 306 · see citing works
Deciphering the astrocyte reaction in Alzheimer's disease
Perez-Nievas, B. G., & Serrano-Pozo, A. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00114 · Cited by 282 · see citing works
“However, apoE4 has been shown to favor Aβ accumulation by promoting its aggregation in the form of amyloid plaques (Hyman et al., 1995) and soluble Aβ oligomers (Hashimoto et al., 2012), and by reducing Aβ clearance (Castellano et al., 2011).”
BackgroundSelf-citationMouse models of Alzheimer’s disease
Esquerda-Canals, G., Montoliu-Gaya, L., Güell-Bosch, J., & Villegas, S. (2017) · Journal of Alzheimer’s Disease · doi:10.3233/jad-170045 · Cited by 288 · see citing works
The path forward in Alzheimer's disease therapeutics: Reevaluating the amyloid cascade hypothesis
Tolar, M., Abushakra, S., & Sabbagh, M. (2020) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2019.09.075 · Cited by 275 · see citing works
“APOE4 carriers, especially patients with homozygous APOE4/4 AD, have a high burden of Ab oligomers [17,19,34], their cognitive status declines more rapidly [35,36], and have less variability in their clinical characteristics.”
BackgroundInfluentialExtracellular protein components of amyloid plaques and their roles in Alzheimer’s disease pathology
Rahman, M. M., & Lendel, C. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00465-0 · Cited by 245 · see citing works
APOE mediated neuroinflammation and neurodegeneration in Alzheimer’s disease
Parhizkar, S., & Holtzman, D. M. (2022) · Seminars in Immunology · doi:10.1016/j.smim.2022.101594 · Cited by 255 · see citing works
Self-citationTolar, M., Hey, J., Power, A., & Abushakra, S. R. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126355 · Cited by 246 · see citing works
“Levels of Aβ oligomers in brains of AD patients with the APOE4/4 genotype were approximately three-fold higher than in APOE4 non-carriers [55,56].”
BackgroundUddin, M. S., Kabir, M. T., Al Mamun, A., Abdel-Daim, M. M., Barreto, G. E., & Ashraf, G. M. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1237-z · Cited by 212 · see citing works
Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease
Najm, R., Jones, E. A., & Huang, Y. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0324-6 · Cited by 183 · see citing works
Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition
Rodriguez, G. A., Tai, L. M., LaDu, M. J., & Rebeck, G. W. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-111 · Cited by 193 · see citing works
Multifaceted roles of APOE in Alzheimer disease
Jackson, R. J., Hyman, B. T., & Serrano-Pozo, A. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00988-2 · Cited by 193 · see citing works
“…222 . c , APOE interacts with the amyloid-β (Aβ) peptide, with APOE4 promoting its oligomerization, fibrillization and seeding into Aβ plaques 113,115,192 and increasing cerebral amyloid angiopathy (CAA) 48 . d , APOE interacts with TREM2 in the microglia plasma membrane and affects…”
Self-citationDevassy, J. G., Leng, S., Gabbs, M., Monirujjaman, M., & Aukema, H. M. (2016) · Advances in Nutrition · doi:10.3945/an.116.012187 · Cited by 184 · see citing works
Hudry, E., Dashkoff, J., Roe, A. D., Takeda, S., Koffie, R. M., Hashimoto, T., Scheel, M., Spires-Jones, T., Arbel-Ornath, M., Betensky, R., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3007000 · Cited by 187 · see citing works
“These results also are consistent with our recent observation that oligomeric Ab is elevated in the CNS of human patients with AD with APOE4 > APOE3 (even when plaque burden is normalized across cases) (26).”
BackgroundResultSelf-citationThe duality of amyloid-β: its role in normal and Alzheimer’s disease states
Azargoonjahromi, A. (2024) · Molecular Brain · doi:10.1186/s13041-024-01118-1 · Cited by 173 · see citing works
“Specifically, individuals with an APOE ε4 allele exhibit a strong association with increased levels of Aβ, including the toxic oligomeric form detected in post-mortem AD brains [271, 272].”
BackgroundSerrano‐Pozo, A., Qian, J., Monsell, S. E., Betensky, R. A., & Hyman, B. T. (2015) · Annals of Neurology · doi:10.1002/ana.24369 · Cited by 176 · see citing works
Self-citationYamazaki, Y., Painter, M. M., Bu, G., & Kanekiyo, T. (2016) · CNS Drugs · doi:10.1007/s40263-016-0361-4 · Cited by 166 · see citing works
The Important Interface Between Apolipoprotein E and Neuroinflammation in Alzheimer’s Disease
Kloske, C. M., & Wilcock, D. M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00754 · Cited by 152 · see citing works
Garai, K., Verghese, P. B., Baban, B., Holtzman, D. M., & Frieden, C. (2014) · Biochemistry · doi:10.1021/bi5008172 · Cited by 145 · see citing works
Self-citationATP-binding cassette transporter A1: From metabolism to neurodegeneration
Koldamova, R., Fitz, N. F., & Lefterov, I. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.05.007 · Cited by 144 · see citing works
Kim, B., Kim, S., Nam, Y., Park, Y., Shin, S. M., & Moon, M. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00465-w · Cited by 150 · see citing works
Kobro-Flatmoen, A., Lagartos-Donate, M. J., Aman, Y., Edison, P., Witter, M. P., & Fang, E. F. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101307 · Cited by 112 · see citing works
“The cause of this may be a direct interaction between ApoE and Aβ monomers which facilitates linking of the latter, in which ApoE4 somehow serves as the best scaffold (Hashimoto et al., 2012).”
APOE-amyloid interaction: Therapeutic targets
Wısnıewskı, T., & Drummond, E. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104784 · Cited by 125 · see citing works
“APOE isotype specific effects have also been observed with regards to the stabilization of Aβ oligomers, where APOE4 was again shown to have the greatest influence (Hashimoto et al., 2012; Garai et al., 2014).”
Hey, J. A., Yu, Y., Versavel, M., Abushakra, S. R., Kočiš, P., Power, A., Kaplan, P. L., Amedio, J. C., & Tolar, M. (2017) · Clinical Pharmacokinetics · doi:10.1007/s40262-017-0608-3 · Cited by 130 · see citing works
“APOE4 homozygotes were also found to have a significantly higher burden of soluble amyloid oligomers compared with non-carriers [17, 18].”
BackgroundIn vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis
Ulrich, J. D., Burchett, J. M., Restivo, J. L., Schuler, D. R., Verghese, P. B., Mahan, T. E., Landreth, G. E., Castellano, J. M., Jiang, H., Cirrito, J. R., et al. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-13 · Cited by 128 · see citing works
“Previous studies indicate that apoE affects the metabolism and oligomerization of Aβ within the brain [3,4,24] as well as influences a variety of other biological processes [2].”
BackgroundSelf-citationMicroglia-Mediated Neuroprotection, TREM2, and Alzheimer’s Disease: Evidence From Optical Imaging
Condello, C., Yuan, P., & Grutzendler, J. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.10.007 · Cited by 131 · see citing works
HSV-1 and Alzheimer’s disease: more than a hypothesis
Piacentini, R., De Chiara, G., Li Puma, D. D., Ripoli, C., Marcocci, M. E., Garaci, E., Palamara, A. T., & Grassi, C. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00097 · Cited by 130 · see citing works
“Similar results were also recently obtained by Hashimoto et al. (2012) who reported that the levels of Aβ oligomers in APOE ε4/ε4 AD brains were 2.7 times higher than those found in APOE ε3/ε3 AD brains, and that ApoE increased Aβ oligomer levels in an isoform-dependent manner (E2 < E3 < E4).”
ResultInfluentialZhang, J., Cao, Q., Li, S., Lu, X., Zhao, Y., Guan, J., Chen, J., Wu, Q., & Chen, G. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.06.043 · Cited by 130 · see citing works
The role of amyloid oligomers in neurodegenerative pathologies
Wells, C., Brennan, S. E., Keon, M., & Ooi, L. (2021) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2021.03.113 · Cited by 124 · see citing works
ApoE and Neurodegenerative Diseases in Aging
Yin, Y., & Wang, Z. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-1117-8_5 · Cited by 111 · see citing works
Synaptic Elimination in Neurological Disorders
Cardozo, P. L., de Lima, I. B. Q., Maciel, E. M. A., Silva, N. C., Dobránsky, T., & Ribeiro, F. M. (2019) · Current Neuropharmacology · doi:10.2174/1570159x17666190603170511 · Cited by 113 · see citing works
Statins and the Brain: More than Lipid Lowering Agents?
Fracassi, A., Marangoni, M., Rosso, P., Pallottini, V., Fioramonti, M., Siteni, S., & Segatto, M. (2018) · Current Neuropharmacology · doi:10.2174/1570159x15666170703101816 · Cited by 116 · see citing works
Soluble apoE/Aβ complex: mechanism and therapeutic target for APOE4-induced AD risk
Tai, L. M., Mehra, S., Shete, V., Estus, S., Rebeck, G. W., Bu, G., & LaDu, M. J. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-2 · Cited by 116 · see citing works
“…& protease digestion stability: NAD > AD Yamauchi et al, 1999 [48] Human CSF & serum (NAD) SDS-PAGE (Non-reducing), WB apoE33/Aβ > apoE44/Aβ (ND) Hashimoto et al, 2012 [27] Human brain (NAD) SEC, SDS-PAGE (Reducing), WB No complex measured, HMW Aβ interacts with apoE on HDL…”
The informed road map to prevention of Alzheimer Disease: a call to arms
McDade, E., Llibre-Guerra, J. J., Holtzman, D. M., Morris, J. C., & Bateman, R. J. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00467-y · Cited by 89 · see citing works
“been implicated in numerous processes, including crosstalk with Aβ [133, 134], tau phosphorylation [126], lipid metabolism, vascular function [135, 136]”
BackgroundSelf-citationZhao, L., Gottesdiener, A. J., Parmar, M., Li, M., Kaminsky, S. M., Chiuchiolo, M. J., Sondhi, D., Sullivan, P. M., Holtzman, D. M., Crystal, R. G., et al. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.04.020 · Cited by 107 · see citing works
“…lipoprotein receptors, and in regulating Ab aggregation, degradation, efflux, and phagocytosis (Castellano et al., 2011; Deane et al., 2008; Hashimoto et al., 2012; Hatters et al., 2006; Holtzman et al., 2012; Li et al., 2012; Manelli et al., 2004; Walker et al., 2000; Yu et al., 2014;…”
Self-citationReduction in DHA transport to the brain of mice expressing human APOE 4 compared to APOE 2
Vandal, M., Alata, W., Tremblay, C., Rioux‐Perreault, C., Salem, N., Calon, F., & Plourde, M. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12640 · Cited by 109 · see citing works
Innate Immunity Fights Alzheimer's Disease
Guillot‐Sestier, M., Doty, K. R., & Town, T. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.08.008 · Cited by 100 · see citing works
Kaji, S., Berghoff, S. A., Spieth, L., Schlaphoff, L., Sasmita, A. O., Vitale, S., Büschgens, L., Kedia, S., Zirngibl, M., Nazarenko, T., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.09.014 · Cited by 104 · see citing works
Keeney, J. T.-R., Ibrahimi, S., & Zhao, L. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-150348 · Cited by 102 · see citing works
Impact of Apolipoprotein E on Alzheimer’s Disease
Hauser, P. S., & Ryan, R. O. (2013) · Current Alzheimer Research · doi:10.2174/15672050113109990156 · Cited by 101 · see citing works
“In another study [66], in vivo and in Hauser and Ryan Page 5”
BackgroundAmyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo
Tai, L. M., Koster, K. P., Luo, J., Lee, S., Wang, Y., Collins, N. C., Aissa, M. B., Thatcher, G. R. J., & LaDu, M. J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.600833 · Cited by 93 · see citing works
Roles of ApoE4 on the Pathogenesis in Alzheimer’s Disease and the Potential Therapeutic Approaches
Sun, Y.-Y., Wang, Z., & Huang, H. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01365-1 · Cited by 95 · see citing works
ABC Transporters Are Key Players in Alzheimer’s Disease
Pereira, C. D., Martins, F., Wiltfang, J., Silva, O. A. B. D. C. E., & Rebelo, S. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170639 · Cited by 93 · see citing works
Aβ propagation and strains: Implications for the phenotypic diversity in Alzheimer's disease
Condello, C., & Stöhr, J. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.03.014 · Cited by 87 · see citing works
“Experimental studies have shown APOE4 to increase levels of oligomeric Aβ (Hashimoto et al. 2012, Tai et al. 2013), and enhance its localization to synaptic compartments (Koffie et al. 2012).”
Kuszczyk, M. A., Sanchez, S., Pankiewicz, J., Kim, J., Duszczyk, M., Guridi, M., Asuni, A. A., Sullivan, P. M., Holtzman, D. M., & Sadowski, M. J. (2013) · The American Journal of Pathology · doi:10.1016/j.ajpath.2013.01.034 · Cited by 89 · see citing works
Self-citationUnderstanding the Role of ApoE Fragments in Alzheimer’s Disease
Muñoz, S. S., Garner, B., & Ooi, L. (2018) · Neurochemical Research · doi:10.1007/s11064-018-2629-1 · Cited by 81 · see citing works
ApoE gene and exceptional longevity: Insights from three independent cohorts
Garatachea, N., Emanuele, E., Calero, M., Fuku, N., Arai, Y., Abe, Y., Murakami, H., Miyachi, M., Yvert, T., Verde, Z., et al. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.02.004 · Cited by 84 · see citing works
“…deposition is the pathological hallmark of AD, oligomeric, soluble forms of Aβ have been implicated as the synaptotoxic component, inwhich higher levels of Aβ oligomers are increasing the loss of dendritic spines and accelerating memory impairments in AD (Hashimoto et al., 2012; Wu et al., 2010).”
BackgroundResultAn in vitro paradigm to assess potential anti-Aβ antibodies for Alzheimer’s disease
Jin, M., O’Nuallain, B., Hong, W., Boyd, J. D., Lagomarsino, V. N., O’Malley, T. T., Liu, W., Vanderburg, C. R., Frosch, M. P., Young‐Pearse, T. L., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05068-w · Cited by 70 · see citing works
Self-citationJackson, R. J., Keiser, M. S., Meltzer, J. C., Fykstra, D. P., Dierksmeier, S. E., Hajizadeh, S., Kreuzer, J., Morris, R., Melloni, A., Nakajima, T., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.03.024 · Cited by 86 · see citing works
Self-citationAmyloid-β dimers in the absence of plaque pathology impair learning and synaptic plasticity
Müller‐Schiffmann, A., Herring, A., Abdel‐Hafiz, L., Chepkova, A. N., Schäble, S., Wedel, D., Horn, A. H. C., Sticht, H., Silva, M. A. D. S., Gottmann, K., et al. (2015) · Brain · doi:10.1093/brain/awv355 · Cited by 80 · see citing works
Donald, J. M. M., O’Malley, T. T., Liu, W., Mably, A. J., Brinkmalm, G., Portelius, E., Wittbold, W. M., Frosch, M. P., & Walsh, D. M. (2015) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2015.01.005 · Cited by 71 · see citing works
“Although, it is unclear whether the Int mwt and High mwt Ab species are homo-oligomers ofAb, or are complexes of Ab bound to other proteins, e.g., APOE [66,67], our data suggest that preventing the formation and further aggregation of Ab dimers may offer a novel target for the treatment of AD.”
BackgroundSelf-citationAmyloid-beta and Alzheimer’s disease: the role of neprilysin-2 in amyloid-beta clearance
Marr, R. A., & Hafez, D. M. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00187 · Cited by 82 · see citing works
“ApoE can affect Aβ in multiple ways including its aggregation, clearance, and catabolism (Bales et al., 1999; Holtzman et al., 2000; Shibata et al., 2000; Fagan et al., 2002; Dolev and Michaelson, 2004; Koistinaho et al., 2004; Manelli et al., 2004; Dodart et al., 2005; Bu, 2009; Belinson et al., 2010; Hashimoto et al…”
LaClair, K. D., Manaye, K. F., Lee, D. L., Allard, J. S., Savonenko, A. V., Troncoso, J. C., & Wong, P. C. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-18 · Cited by 83 · see citing works
“Individuals with APOE4 have a pronounced increase in Aβ oligomerization [5] and AD incidence [6,7] relative to carriers of the other APOE alleles.”
BackgroundEtiology and Pathogenesis of Late-Onset Alzheimer’s Disease
Balin, B. J., & Hudson, A. P. (2014) · Current Allergy and Asthma Reports · doi:10.1007/s11882-013-0417-1 · Cited by 79 · see citing works
Wen, J., Satyanarayanan, S. K., Li, A., Yan, L., Zhao, Z., Yuan, Q., Su, K., & Su, H. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.10.018 · Cited by 84 · see citing works
“…have highlighted that compared to ApoE2 and ApoE3, ApoE4 not only promotes the seeding of A β peptide into oligomers, protofibrils, and fibrils (Hashimoto et al., 2012; Hori et al., 2015; Liu et al., 2017) but also hinders the enzymatic degradation of A β (Deane et al., 2008) and its clearance…”
BackgroundLewandowski, C. T., Maldonado Weng, J., & LaDu, M. J. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104811 · Cited by 72 · see citing works
“Across studies, Aβ deposition, soluble oAβ levels, and amyloid plaque pathology are consistently elevated in human AD brain samples in the presence of apoE4 compared to other isoforms (Tai et al., 2013; Hashimoto et al., 2012; Koffie et al., 2012; Hoglund et al., 2017).”
BackgroundYashin, A. I., Fang, F., Kovtun, M., Wu, D., Duan, M., Arbeev, K. G., Akushevich, I. V., Kulminski, A. M., Culminskaya, I. V., Zhbannikov, I. Y., et al. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.10.020 · Cited by 72 · see citing works
“Many studies confirm the presence of such interaction, however, explanations of its nature differ considerably from one study to the next (LaDu et al., 1994; Hashimoto et al., 2012; Manelli et al., 2004; Cerf et al., 2011; Carter, 2005).”
BackgroundRemembering your A, B, C's: Alzheimer's disease and ABCA1
Lewandowski, C. T., Laham, M. S., & Thatcher, G. R. J. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.01.011 · Cited by 76 · see citing works
Hori, Y., Takeda, S., Cho, H., Wegmann, S., Shoup, T. M., Takahashi, K., Irimia, D., Elmaleh, D. R., Hyman, B. T., & Hudry, E. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.586602 · Cited by 78 · see citing works
“As reported previously, oligomeric A or A peptides associated with other unidentified molecules may interfere with the interaction with anti-A detection antibodies, therefore altering the outcome of these ELISA systems (37).”
BackgroundMethodInfluentialSelf-citationNeurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors
Lecordier, S., Manrique‐Castano, D., Moghrabi, Y. E., & ElAli, A. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.727590 · Cited by 76 · see citing works
“Moreover, ApoE4 increases the formation of Aβ oligomers, which are now well established to constitute the most neurotoxic form of Aβ (Hashimoto et al., 2012; Youmans et al., 2012).”
BackgroundInflammation: Bridging Age, Menopause and APOEε4 Genotype to Alzheimer’s Disease
Mishra, A., & Brinton, R. D. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00312 · Cited by 69 · see citing works
Hey, J. A., Kočiš, P., Hort, J., Abushakra, S. R., Power, A., Vyhnálek, M., Yu, Y., & Tolar, M. (2018) · CNS Drugs · doi:10.1007/s40263-018-0554-0 · Cited by 73 · see citing works
Qian, J., Betensky, R. A., Hyman, B. T., & Serrano-Pozo, A. (2021) · Neurology · doi:10.1212/wnl.0000000000011883 · Cited by 71 · see citing works
Self-citationTakeda, S., Hashimoto, T., Roe, A. D., Hori, Y., Spires‐Jones, T. L., & Hyman, B. T. (2013) · The FASEB Journal · doi:10.1096/fj.13-229666 · Cited by 72 · see citing works
Self-citationPiccialli, I., Tedeschi, V., Caputo, L., D’Errico, S., Ciccone, R., De Feo, V., Secondo, A., & Pannaccione, A. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.876614 · Cited by 73 · see citing works
Talwar, P., Sinha, J., Grover, S., Rawat, C., Kushwaha, S. S., Agarwal, R., Taneja, V., & Kukreti, R. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9390-0 · Cited by 70 · see citing works
Liu, M., Paranjpe, M. D., Zhou, X., Duy, P. Q., Goyal, M. S., Benzinger, T. L. S., Lu, J., Wang, R., & Zhou, Y. (2019) · Theranostics · doi:10.7150/thno.35366 · Cited by 65 · see citing works
“ApoE ε4 carriers exhibit faster cognitive decline [3, 4], increased amyloid β deposition [5], higher NFT density [6] and increased glucose hypometabolism [7] than ApoE ε4 non-carriers.”
Ceramides and sphingomyelinases in senile plaques
Panchal, M., Gaudin, M., Lazar, A. N., Salvati, E., Rivals, I., Ayciriex, S., Dauphinot, L., Dargère, D., Auzeil, N., Masserini, M., et al. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.01.010 · Cited by 68 · see citing works
Kang, M. K., Lee, J., Nguyen, A. H., & Sim, S. J. (2015) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2015.05.017 · Cited by 69 · see citing works
Role of Apolipoprotein E in β-Amyloidogenesis
Hori, Y., Hashimoto, T., Nomoto, H., Hyman, B. T., & Iwatsubo, T. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.622209 · Cited by 66 · see citing works
Self-citationApolipoprotein E in Alzheimer’s disease trajectories and the next-generation clinical care pathway
Narasimhan, S., Holtzman, D. M., Apostolova, L. G., Cruchaga, C., Masters, C. L., Hardy, J., Villemagne, V. L., Bell, J. S., Cho, M., & Hampel, H. J. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01669-5 · Cited by 70 · see citing works
“In humans, APOE ε4 carriers have greater amounts of soluble Aβ oligomers 59,60 , with ApoE4 increasing Aβ oligomerization in vitro 60 , while ApoE2 and ApoE3 inhibit the conver sion of protofibrils into fibrils 61 .”
Self-citationMichno, W., Wehrli, P. M., Zetterberg, H., Blennow, K., & Hanrieder, J. (2018) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2018.09.010 · Cited by 59 · see citing works
Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease
Xia, Z., Prescott, E. E., Urbanek, A., Wareing, H. E., King, M. C., Olerinyova, A., Dakin, H., Leah, T., Barnes, K. A., Matuszyk, M. M., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49028-z · Cited by 67 · see citing works
“This fi nding supports the previous report that APOE4 carriers have more diffusible A β aggregates than APOE3 carriers 42,43 .”
ResultSelf-citationWilkins, H., Koppel, S. J., Bothwell, R. J., Mahnken, J. D., Burns, J. M., & Swerdlow, R. H. (2017) · Redox Biology · doi:10.1016/j.redox.2017.04.010 · Cited by 61 · see citing works
The ApoE Gene Is Related with Exceptional Longevity: A Systematic Review and Meta-Analysis
Garatachea, N., Marin, P. J., Santos‐Lozano, A., Sanchis‐Gomar, F., Emanuele, E., & Lucía, A. (2014) · Rejuvenation Research · doi:10.1089/rej.2014.1605 · Cited by 59 · see citing works
Pankiewicz, J. E., Guridi, M., Kim, J., Asuni, A. A., Sanchez, S., Sullivan, P. M., Holtzman, D. M., & Sadowski, M. J. (2014) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0075-0 · Cited by 57 · see citing works
Self-citationLiu, S., Park, S.-A., Allington, G., Prelli, F. C., Sun, Y., Martá-Ariza, M., Scholtzova, H., Biswas, G. K., Brown, B., Verghese, P. B., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-08604-8 · Cited by 57 · see citing works
Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer’s disease
Serrano-Pozo, A., Li, Z., Noori, A., Nguyen, H. N., Mezlini, A., Li, L., Hudry, E., Jackson, R. J., Hyman, B. T., & Das, S. (2021) · Nature Aging · doi:10.1038/s43587-021-00123-6 · Cited by 49 · see citing works
Self-citationAll Together Now: Modeling the Interaction of Neural With Non-neural Systems Using Organoid Models
Chukwurah, E., Osmundsen, A. M., Davis, S. W., & Lizarraga, S. B. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00582 · Cited by 51 · see citing works
“In humans, the APOE gene has three polymorphic alleles: APOE2, APOE3, and APOE4, each with different binding affinities for Aβ plaques (Hashimoto et al., 2012).”
BackgroundInitiative, A. D. N., Liu, Y., Tan, L., Wang, H.-F., Liu, Y., Hao, X., Tan, C., Jiang, T., Liu, B., Zhang, D., et al. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9388-7 · Cited by 51 · see citing works
Madhu, P., & Mukhopadhyay, S. (2021) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30141 · Cited by 50 · see citing works
“Lipidated apoE is known to increase the amount of Aβ oligomers in AD patients.(124) A recent study shows that Aβ oligomers strongly interact with the full‐length apoE than small segments of apoE, suggesting that the high binding affinity is mediated via multivalent interactions.”
BackgroundHu, M. L., Quinn, J., & Xue, K. (2021) · Life · doi:10.3390/life11070635 · Cited by 50 · see citing works
“APOE isoforms have been proposed to have differential effects on key aspects of Aβ biology, including (i) binding and clearance [79,80], (ii) oligomer stabilisation [81,82] and (iii) APP transcription and Aβ secretion [83].”
BackgroundGenetic risk factors for Alzheimer disease: emerging roles of microglia in disease pathomechanisms
Takatori, S., Wang, W., Iguchi, A., & Tomita, T. (2019) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-030-05542-4_5 · Cited by 44 · see citing works
- Authors
- Hashimoto, T., Serrano-Pozo, A., Hori, Y., Adams, K. W., Takeda, S., Banerji, A. O., Mitani, A., Joyner, D., Thyssen, D. H., Bacskai, B. J., Frosch, M. P., Spires-Jones, T. L., Finn, M. B., Holtzman, D. M., & Hyman, B. T.
- Affiliations
- Massachusetts General Hospital (US)
- Washington University in St. Louis (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-10-24
- Volume
- 32
- Issue
- 43
- Pages
- 15181-15192
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3493562
- OpenAlex
- W1966895399
- Cited by
- 294
- References
- 44
- Citations by year
- 2026: 18 · 2025: 24 · 2024: 24 · 2023: 15 · 2022: 32 · 2021: 29 · 2020: 22 · 2019: 30 · 2018: 16 · 2017: 20 · 2016: 7 · 2015: 17 · 2014: 23 · 2013: 16 · 2012: 1
- FWCI
- 12.23
- 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)
- Europe PMC (PubMed Central) (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health
- Japan Society for the Promotion of Science (24800015)
- National Institute on Aging (R01AG013956, RC1AG036265, R00AG033670, AG 12406, R37AG012406, AG033670, P50AG005134, R37AG013956, AG13956, K99AG033670, P30AG062421, R01AG012406)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E, APOE ε4, amyloid-beta, Alzheimer's disease, APOE isoforms, dendritic spine loss, memory impairment, genetic risk factors
- MeSH terms
- Alzheimer Disease, Analysis of Variance, Astrocytes, Brain, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Peptide Fragments, Transfection, Amyloid beta-Peptides, Protein Isoforms, Green Fluorescent Proteins, Lipid Metabolism, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2, HEK293 Cells, Morpholinos
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