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Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease
Open accessAbstract
APOE genotype is a major genetic risk factor for late-onset Alzheimer disease (AD). ABCA1, a member of the ATP-binding cassette family of active transporters, lipidates apoE in the CNS. Abca1(-/-) mice have decreased lipid associated with apoE and increased amyloid deposition in several AD mouse models. We hypothesized that mice overexpressing ABCA1 in the brain would have increased lipidation of apoE-containing lipoproteins and decreased amyloid deposition. To address these hypotheses, we created PrP-mAbca1 Tg mice that overexpress mouse Abca1 throughout the brain under the control of the mouse prion promoter. We bred the PrP-mAbca1 mice to the PDAPP AD mouse model, a transgenic line overexpressing a mutant human amyloid precursor protein. PDAPP/Abca1 Tg mice developed a phenotype remarkably similar to that seen in PDAPP/Apoe(-/-) mice: there was significantly less amyloid beta-peptide (Abeta) deposition, a redistribution of Abeta to the hilus of the dentate gyrus in the hippocampus, and an almost complete absence of thioflavine S-positive amyloid plaques. Analyses of CSF from PrP-mAbca1 Tg mice and media conditioned by PrP-mAbca1 Tg primary astrocytes demonstrated increased lipidation of apoE-containing particles. These data support the conclusions that increased ABCA1-mediated lipidation of apoE in the CNS can reduce amyloid burden and that increasing ABCA1 function may have a therapeutic effect on AD.
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TL;DR
Overexpression of ABCA1 in the brain increased lipidation of apoE-containing lipoproteins and markedly reduced fibrillar amyloid deposition in PDAPP mice. The phenotype resembled PDAPP/Apoe−/− mice, supporting ABCA1/apoE lipidation as a potential AD therapeutic target.
Key findings
- PrP-mAbca1 transgenic mice overexpressed ABCA1 throughout the brain at approximately 2- to 14-fold across five lines; when crossed to PDAPP mice, PDAPP/Abca1 Tg mice had significantly less Aβ deposition, redistribution of Aβ to the hilus of the dentate gyrus, and almost no thioflavine S–positive amyloid plaques, similar to PDAPP/Apoe−/− mice.
- At 12 months, Aβ levels were approximately 2.5-fold lower in PDAPP/Abca1 line D and approximately 3-fold lower in line E versus non-Tg littermates; thioflavine S–positive amyloid was decreased by approximately 50% with 2-fold ABCA1 overexpression and to almost 0 with 6-fold or greater overexpression.
- At 3 months, before histological Aβ deposition, PDAPP/Abca1 line D and E Tg mice had 15%–50% higher Aβ levels than non-Tg controls, with no differences in APP or APP C-terminal fragments, suggesting altered clearance/transport rather than increased production.
- ABCA1 overexpression increased apoE lipidation: CSF apoE particles tended to be larger, astrocyte-conditioned media had a greater proportion of apoE particles larger than 11 nm, and lipoprotein fractions showed a significantly greater cholesterol-to-apoE ratio. High-expressing lines also had lower apoE in hippocampus (approximately 40%) and CSF (approximately 40%–70%), but line D reduced Aβ without lowering apoE.
Methods
- Mouse Abca1 cDNA was cloned into the MoPrP.HD-N171 vector to create PrP-mAbca1 Tg mice; five lines (D, E, L, J, G) with 2- to 14-fold brain ABCA1 overexpression were characterized, and lines D, E, and J were bred to the PDAPP AD mouse model.
- Mice were analyzed at 3 or 12 months with non-Tg littermate controls; outcomes included Aβ and thioflavine S histology/stereology, Aβ and apoE ELISAs, Western blotting, real-time RT-PCR, CSF and astrocyte-conditioned media lipoprotein analyses by nondenaturing gradient gel electrophoresis and size-exclusion chromatography, and testis histology/TUNEL/immunohistochemistry.
- Statistical comparisons used two-tailed Student’s t test or Mann-Whitney U test, with P < 0.05 considered significant.
Limitations
- The paper states that it is unclear whether increasing ABCA1 in adulthood may compromise male fertility, or whether ABCA1 can be selectively targeted to brain versus testes or other organs; male mice overexpressing ABCA1 at 6-fold or greater were infertile, with approximately 50% reduced testes mass and approximately 3-fold more apoptotic testicular cells.
- The paper notes that mechanisms linking increased apoE lipidation to altered Aβ transport, clearance, or aggregation were not directly tested, and that behavioral studies in APP Tg mice can be difficult to interpret.
- Evident from the text: findings are from transgenic mouse models with supraphysiological ABCA1 overexpression, some high-expressing lines had peripheral cholesterol changes of unknown mechanism, and several supporting observations are reported as data not shown.
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29 Own result · 19 Own interpretation · 9 Sources not found · 2 No basis given · 1 Own method
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In the paper
“ranging from approximately 2-fold in line D to approximately 14-fold in line G (Figure 1A).”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > The 5 lines of PrP-mAbca1
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Analysis of tissue from the occipital cortex, frontal cortex, hippocampus, cerebellum, striatum, septum, and thalamus showed that PrP-mAbca1 Tg mice overexpressed ABCA1 throughout the brain (Figure 1B).”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > The 5 lines of PrP-mAbca1
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In the CSF, apoE levels were decreased by approximately 40%-70% in all lines overexpressing ABCA1 (Figure 6C).”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > ApoE levels and solubility in PrP-mAbca1 Tg mice.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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In the paper
“We found no difference between Tg and non-Tg apoE mRNA levels in either the hippocampus or cortex of either line (Figure 6D and data not shown).”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > ApoE levels and solubility in PrP-mAbca1 Tg mice.
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“overexpression of ABCA1 by 6-fold or greater resulted in reductions in hippocampal apoE of approximately 40% compared with non-Tg littermate control mice (Figure 6A).”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > ApoE levels and solubility in PrP-mAbca1 Tg mice.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“Quantification of the APP and CTF bands using image analysis software revealed no significant differences between PDAPP/Abca1 Tg and PDAPP/ Abca1 non-Tg mice.”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Statistics.
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Compared with astrocytes derived from non-Tg mice, astrocytes derived from Tg mice secreted less apoE and associated cholesterol in HDL-like lipoproteins (Figure 7, C and D).”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > ApoE levels and solubility in PrP-mAbca1 Tg mice.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Spermatogenesis defects in 3-month-old PrP-mAbca1 line E Tg mice.”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Statistics.
plainn = 5- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In addition to the positive effects of overexpression of ABCA1 on Aβ, we did observe that male mice overexpressing ABCA1 at levels 6-fold or greater than those in normal brain were infertile.”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“No elongated spermatids were present in testes from Tg mice.”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Statistics.
plainn = 5- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 16
- Probably not a substantial claim. 4
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In the paper
“The PDAPP mice with wild-type ABCA1 levels (PDAPP/Abca1 non-Tg mice) had frequent punctate Aβ deposits in the cortex and hippocampus (Figure 3A, top left panel), including the molecular layer of the hippocampus, but almost no Aβ deposits in the hilus of the dentate gyrus of the hippocampus (Figure 3A, middle left panel).”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Amyloid deposition in the brains of PDAPP/Abca1 Tg mice.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In contrast, the PDAPP mice with ABCA1 overexpression (PDAPP/Abca1 Tg mice) had rare Aβ deposition in the cortex (Figure 3A, top middle panel), occasional Aβ deposition in the molecular layer, and frequent Aβ deposition in the hilus of the dentate gyrus (Figure 3A, middle panel).”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Amyloid deposition in the brains of PDAPP/Abca1 Tg mice.
plain- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Since decreases or increases in ABCA1 expression alter the absolute level of apoE without affecting Apoe transcription, understanding how ABCA1 alters apoE metabolism in the brain will be important.”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“However, almost no thioflavine S-positive amyloid plaques were seen in the PDAPP/Abca1 Tg mice (Figure 3A, bottom middle panel) or in PDAPP/Apoe -/-mice (Figure 3A, bottom right panel), even in sections with extensive Aβ deposits.”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Amyloid deposition in the brains of PDAPP/Abca1 Tg mice.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the cortex, apoE was decreased by only approximately 20% in Tg mice from PrP-mAbca1 lines L, J, and G and was not decreased significantly in lines D or E (Figure 6B).”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > ApoE levels and solubility in PrP-mAbca1 Tg mice.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The Aβ load in the entire hippocampus did not vary significantly according to the presence of the mABCA1 transgene, but the distribution of Aβ within the hippocampus was altered by the transgene.”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Amyloid deposition in the brains of PDAPP/Abca1 Tg mice.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PDAPP/Abca1 Tg mice had more Aβ deposition in the hilus of the dentate gyrus and less in the molecular layer (Figure 4A).”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Amyloid deposition in the brains of PDAPP/Abca1 Tg mice.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that PDAPP/Abca1 Tg mice had (a) decreased deposition of Aβ; (b) a near absence of thioflavine S-positive amyloid plaques; and (c) a redistribution of Aβ deposits in the hippocampus from the molecular layer to the hilus of the dentate gyrus.”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“APP Tg mice that are crossed to mice lacking Apoe develop significantly less Aβ deposition, and strikingly, the Aβ plaques that do form are almost all nonfibrillar and are not associated with neuritic dystrophy (20,23,24).”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Introduction
What the sources say
- Not matchedcites [20]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [23]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“3 laboratories independently found that deletion of Abca1 either has no effect on or even increases Aβ deposition in 4 different mouse models of AD (20,23,24).”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Introduction
What the sources say
- Not matchedcites [20]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [23]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“demonstrating that lipid-poor apoE binds to fibrillar Aβ in vivo and likely promotes amyloidogenesis.”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Introduction
What the sources say
- Not matchedcites [23]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To control for genetic background effects, non-Tg littermate mice were always used as controls in experiments with the PrP-mAbca1 Tg mice from the appropriate line.”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Animals and tissue collection.
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The size of the decrease did not vary between lines that overexpressed ABCA1 6-fold to 14-fold, indicating that the effect is saturable.”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > ApoE levels and solubility in PrP-mAbca1 Tg mice.
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Activation of the transcription factor LXR has been shown to increase transcription of ABCA1 and many other genes involved in lipid metabolism and other pathways (50)(51)(52).”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Discussion
What the sources say
- Not matchedcites (50)(51)(52)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This phenotype strongly argues that overexpression of ABCA1 in the brain decreases the amyloidogenic properties of apoE and, further, that increased apoE lipidation results in a phenotype very similar to apoE deficiency with respect to Aβ metabolism.”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The PDAPP mouse model of AD recapitulates key features of human AD such that findings in this model are relevant to AD.
- Rests on an assumption: Aβ deposition and fibrillogenesis in mouse models are appropriate measures of AD pathology.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because this difference in apoJ levels was not observed in ABCA1 line D mice (data not shown), a 2-fold overexpression of ABCA1 in the brain is insufficient to significantly alter either apoJ or apoE levels (Figure 6A).”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Effects of brain overexpression of ABCA1 on other proteins.
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In addition, lipidated apoE binds with a much higher affinity than poorly lipidated apoE to soluble Aβ (60).”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Discussion
What the sources say
- Not matchedcites [60]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Previous in vitro work has shown that lipidated apoE forms an SDS-stable complex with Aβ to a greater extent than nonlipidated apoE (58,59).”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Discussion
What the sources say
- Not matchedcites [58]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [59]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These higher levels do not represent deposited Aβ, as the mice did not have histological evidence of Aβ deposition at this age.”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Amyloid deposition in the brains of PDAPP/Abca1 Tg mice.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There were no differences between PDAPP/Abca1 line E Tg and PDAPP/non-Tg mice (Figure 5E), suggesting that Aβ production was not likely to account for the differences in Aβ levels at 3 months.”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Amyloid deposition in the brains of PDAPP/Abca1 Tg mice.
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
The PDAPP mouse model of AD recapitulates key features of human AD such that findings in this model are relevant to AD.
“PDAPP AD mouse model, a transgenic line overexpressing a mutant human amyloid precursor protein.”
“increasing ABCA1 function may have a therapeutic effect on AD.”
The paper relies on this without support.
Aβ deposition and fibrillogenesis in mouse models are appropriate measures of AD pathology.
“These data support the conclusions that increased ABCA1-mediated lipidation of apoE in the CNS can reduce amyloid burden and that increasing ABCA1 function may have a therapeutic effect on AD.”
The paper relies on this without support.
The effects of ABCA1 overexpression on Aβ deposition are not due to altered expression of other proteins outside those tested.
“No differences were found in the levels of low-density lipoprotein receptor (LDLR), LDLR-related protein 1 (LRP1), and apoA-I when comparing ABCA1 line E Tg mice to non-Tg littermates (Figure 8, A and B).”
Claims other papers make about this one
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The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Conversely, increasing Abca1 expression, and subsequently apoE lipidation, reduces Aβ peptides and plaque deposition. 13”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [13]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“ABCA1 overexpression or LXR/RXR agonist treatment decreased amyloid deposition [66-69].”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [69]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Both the overexpression and deletion of ABCA1 in the mouse brain resulted in a decrease in apoE protein level [28-30].”
From Measurement of apolipoprotein E and amyloid β clearance rates in the mouse brain using bolus stable isotope labeling (2012) · cites this paper as [30]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, the apoE containing lipoprotein particles isolated from the cerebral spinal fluid (CSF) of ABCA1−/− mice were poorly lipidated, while those from the CSF of mice overexpressing ABCA1 had higher levels of lipidation compared to Wt animals [28,30].”
From Measurement of apolipoprotein E and amyloid β clearance rates in the mouse brain using bolus stable isotope labeling (2012) · cites this paper as [30]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In addition, several studies have demonstrated that increasing apoE lipidation, either through genetic or pharmacological approaches, promotes Aβ clearance and improves cognitive performance in mice (27, 44, 45).”
From APOE3 -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [44]
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“because the extent of apoE lipidation may also play a role in modulating Aβ accumulation (41)”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [41]
The cited source says what the claim attributes to it.
In the citing paper
“This finding is consistent with a previous report that demonstrated no change in apoE protein levels when ABCA1 was overexpressed 2‐ or 6‐fold over the endogenous level in the cortex. 13”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“ABCA1 gene ablation in mice decreased APOE lipidation and levels and increased Aβ accumulation in APP transgenic mouse models.”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [69]
The cited source says what the claim attributes to it.
In the citing paper
“whereas ABCA1 overexpression ameliorated Aβ accumulation (Donkin et al., 2010; Wahrle et al., 2008).”
From miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression (2012) · cites this paper as Wahrle et al., 2008
The cited source says what the claim attributes to it.
In the citing paper
“In the brain, the level of ABCA1 has been shown to modulate the extent of apoE lipidation and apoE levels.”
From Measurement of apolipoprotein E and amyloid β clearance rates in the mouse brain using bolus stable isotope labeling (2012) · cites this paper as [30]
The cited source says what the claim attributes to it.
In the citing paper
“Brain levels of the cholesterol transporter ATP binding cassette A1 (ABCA1) also alter the amount of apoE and the extent of apoE lipidation in mice.”
From Measurement of apolipoprotein E and amyloid β clearance rates in the mouse brain using bolus stable isotope labeling (2012) · cites this paper as [30]
The cited source says what the claim attributes to it.
In the citing paper
“In transgenic mice that overexpress the human amyloid precursor protein (APP), increasing ABCA1 levels caused a significant decrease in amyloid deposition in the brain [30].”
From Measurement of apolipoprotein E and amyloid β clearance rates in the mouse brain using bolus stable isotope labeling (2012) · cites this paper as [30]
The cited source says what the claim attributes to it.
In the citing paper
“ATP-binding cassette transporter A1 (ABCA1) overexpression in APP transgenic mice also showed a similar phenotype (Wahrle et al., 2008).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Wahrle et al., 2008
The cited source says what the claim attributes to it.
In the citing paper
“When these mice, which had greater apoE lipidation, were crossed with PDAPP mice, there was a dramatic decrease in the amount of Aβ deposition and thioflavine-S positive plaques in the ABCA1 transgenic mice (Wahrle et al., 2008).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Wahrle et al., 2008
The cited source says what the claim attributes to it.
In the citing paper
“Over a decade of evidence demonstrates that the cell-surface lipid transporter ATP binding cassette subfamily A member 1 (ABCA1) modulates AD pathogenesis, with ABCA1 antagonism increasing, and agonism decreasing, pathology [48–51].”
From Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation (2023) · cites this paper as [49]
The cited source says what the claim attributes to it.
In the citing paper
“Furthermore, overexpressing ABCA1 increases the percentage of lipidated ApoE fractions and reduces A accumulation (Wahrle et al., 2008).”
From ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes (2019) · cites this paper as Wahrle et al., 2008
The cited source says what the claim attributes to it.
In the citing paper
“In contrast, overexpression of ABCA1 led to a decrease in Aβ plaques (Fig. 2B) [43].”
From ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer’s disease and related disorders (2026) · cites this paper as [43]
The cited source says what the claim attributes to it.
In the citing paper
“This transporter is of prime interest in AD because its impact on brain cholesterol metabolism modulates the brain's amyloid burden.”
The cited source says what the claim attributes to it.
In the citing paper
“In a mouse model, improved ApoE lipidation by the overexpression of ATP-binding cassette transporter family member A1 (ABCA1) decreased plaque deposition (Wahrle et al., 2005; Wahrle et al., 2008; Wahrle et al., 2004).”
From NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load (2021) · cites this paper as Wahrle et al., 2008
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Previous research has shown that the overexpression of ABCA1 ameliorated Aβ pathology in a mouse model of Aβ amyloidosis and that treatment with an LXR agonist was protective in a mouse model of tau-mediated neurodegeneration (65, 66).”
From Lipidome and proteome of astrocyte and microglia ApoE lipoprotein reveal differences based on cell type and ApoE isoform (2026) · cites this paper as [66]
Experimental — accuracy not yet measuredIn the citing paper
“Whereas overexpression of ABCA1 decreases the amyloid accumulation [14]”
In the citing paper
“whereas overexpression of the gene decreases amyloid deposition and improves the animals' behavior [14].”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“| +, n = 11 | 0.23 ± 0.09 | 0.35 ± 0.08 | 0.05 ± 0.07 | 0.86 ± 0.13 | 0.73 ± 0.12 | 1.21 ± 0.11 |”
§ Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease > Statistics.
Reported 0.73 · recomputed 0.28
Citations
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Cited by
Sorted by citations
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661
Self-citationApolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425
Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance
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“Moreover, because the extent of apoE lipidation may also play a role in modulating Aβ accumulation (41), we assessed the size of lipidated apoE particles from the CSF of young and old PDAPP/TRE mice by native polyacrylamide gel electrophoresis (PAGE)/Western blot analysis.”
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
ApoE Promotes the Proteolytic Degradation of Aβ
Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.010 · Cited by 876
“The present study provides a mechanistic explanation of both the effects of Abca1 inactivation (or overexpression; Wahrle et al., 2008) and the Nrlh3 and Nrlh2 knockouts (Zelcer et al.”
BackgroundSelf-citationApolipoprotein E: from cardiovascular disease to neurodegenerative disorders
Mahley, R. W. (2016) · Journal of Molecular Medicine · doi:10.1007/s00109-016-1427-y · Cited by 837
“Overexpression of ABCA1 in an AD mouse model reduces amyloid deposition and improves A β clearance [59].”
Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease
Holtzman, D. M., Herz, J., & Bu, G. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006312 · Cited by 782
“…APP Tg mice are crossed onto an Abca12/2 background, this decreases apoE lipidation and increases amyloid deposition (Hirsch-Reinshagen et al. 2005; Koldamova et al. 2005a; Wahrle et al. 2005), whereas increasing ABCA1 increases apoE lipidation and decreases amyloid deposition (Wahrle et al. 2008).”
BackgroundSelf-citationThe role of microglia in amyloid clearance from the AD brain
Lee, C. Y. D., & Landreth, G. E. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0433-4 · Cited by 701
“On the other hand, overexpression of ABCA1 in the brain of PDAPP mouse model of AD reduced amyloid deposition (Wahrle et al. 2008).”
BackgroundAnimal models of Alzheimer's disease and frontotemporal dementia
Götz, J., & Ittner, L. M. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2420 · Cited by 676
“Transgenic ABCA1 overexpression in PDAPP mice significantly reduced Aβ levels and plaque burde”
BackgroundApoE 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
The Role of Metabolic Disorders in Alzheimer Disease and Vascular Dementia: Two Roads Converged
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“Highly lipidated apoE increases A brain efflux, thereby reducing A deposition, and poorly lipidated apoE increases the amyloid burden.(34) The lipidation status of peripheral A may also affect its clearance.”
BackgroundCholesterol metabolism in neurons and astrocytes
Pfrieger, F. W., & Ungerer, N. (2011) · Progress in Lipid Research · doi:10.1016/j.plipres.2011.06.002 · Cited by 500
Lipids and Alzheimer’s Disease
Kao, Y.-C., Ho, P.-C., Tu, Y.-K., Jou, I.-M., & Tsai, K.-J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041505 · Cited by 485
Apolipoprotein 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
“Poorly lipidated APOE promotes amyloidogenesis in AD mouse models (Wahrle et al. 2005), whereas selective ABCA1 overexpression is sufficient to block amyloid plaque formation (Wahrle et al. 2008).”
BackgroundApolipoprotein E, Receptors, and Modulation of Alzheimer’s Disease
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“Consistent with these findings, overexpression of ABCA1 in AD mice reduced amyloid deposition (Wahrle et al., 2008).”
ResultAPOE ε4: The most prevalent yet understudied risk factor for Alzheimer's disease
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“In addition, studies utilizing cell cultures and corresponding mice that overexpress the key apoE-lipidating protein ABCA1, suggest that increasing the lipidation of apoE lowers its interaction with Ab [32].”
BackgroundInfluentialApolipoprotein E: From lipid transport to neurobiology
Hauser, P. S., Narayanaswami, V., & Ryan, R. O. (2011) · Progress in Lipid Research · doi:10.1016/j.plipres.2010.09.001 · Cited by 320
ApoE Cascade Hypothesis in the pathogenesis of Alzheimer’s disease and related dementias
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“Supporting this, Abca1-knockout increases [244], whereas Abca1-overexpression decreases Aβ deposition in PDAPP mouse models [245].”
BackgroundAstrogliosis: An integral player in the pathogenesis of Alzheimer's disease
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“4b. ABCA1 is important for the proper lipidation of ApoE (Wahrle et al., 2004); a process that when lacking leads to increased Ab deposition so when this transporter is overexpressed in transgenic AD mice it was found to reduce the deposition of Ab plaques (Wahrle et al., 2008).”
BackgroundApolipoprotein 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
Self-citationPPARγ Agonists as Therapeutics for the Treatment of Alzheimer's Disease
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“Conversely, overexpression of human Abca1 in mice resulted in reduced A levels and plaque burden.(96) Importantly, the expression of the Abca1 gene is transcriptionally regulated by the nuclear receptors, liver X receptors (LXRs), PPAR , and RXR.”
BackgroundHuman APOE Isoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice
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“Conversely, when ABCA1 is overexpressed, apoE appears to be maximally lipidated, and brain A burden is significantly reduced (Wahrle et al., 2008).”
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“ABCA1 has been shown to play key roles in apoE lipidation and A b clearance in AD.”
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Regulation of cholesterol homeostasis
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“whereas ABCA1 overexpression ameliorates amyloid plaque formation [109, 110].”
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“[173] stated that ABCA1 deletion could upsurge the deposition of Aβ peptide.”
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Cholesterol involvement in the pathogenesis of neurodegenerative diseases
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“By contrast, in transgenic mice overexpressing ABCA1, the increased ABCA1 function significantly decreases Aβ deposition (Wahrle et al., 2008).”
BackgroundKim, J., Jiang, H., Park, S., Eltorai, A. E. M., Stewart, F. R., Yoon, H., Basak, J. M., Finn, M. B., & Holtzman, D. M. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.3773-11.2011 · Cited by 204
Self-citationRole of the Blood–Brain Barrier in the Nutrition of the Central Nervous System
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“On the other hand, PDAPP/abca1 transgenic mice overexpressing both a mutant human amyloid precursor protein and ABCA1 transporter have reduced amyloid-b burden in brain parenchyma and scarce vascular amyloid-b deposits (191).”
ApoE Lipidation as a therapeutic target in Alzheimer’s disease
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The Role of APOE and TREM2 in Alzheimer′s Disease—Current Understanding and Perspectives
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“Conversely, overexpression of Abca1 increases APOE lipidation and decreases amyloid deposition [144].”
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“…an altered interaction between ApoE and A , influenced by the ApoE lipidation status, might be partially responsible for the reduction of insoluble A in TO901317-treated mice, similar to the proposed mechanism of plaque reduction in PDAPP mice overexpressing ABCA1 (Wahrle et al., 2008).”
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“From these findings, it is speculated that increase in lipidation state of apoE or increased ABCA1 activity may facilitate A clearance (or reduce A deposits), and this approach could be a potential therapeutic strategy for AD [137, 140, 142-144].”
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Self-citationFormation and function of apolipoprotein E-containing lipoproteins in the nervous system
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Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation
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Self-citationDevelopment of Novel Therapeutics Targeting the Blood–Brain Barrier: From Barrier to Carrier
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ABCA1 and ABCG1 as potential therapeutic targets for the prevention of atherosclerosis
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miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression
Kim, J., Yoon, H., Ramírez, C. M., Lee, S.-M., Hoe, H.-S., Fernández-Hernando, C., & Kim, J. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2011.11.010 · Cited by 173
“ABCA1 deficiency leads to an increase in Aβ and amyloid deposition (Hirsch-Reinshagen et al., 2005; Koldamova et al., 2005;Wahrle et al., 2005) whereas ABCA1 overexpression ameliorated Aβ accumulation (Donkin et al., 2010; Wahrle et al., 2008).”
BackgroundSelf-citationTherapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease
Williams, T., Borchelt, D., & Chakrabarty, P. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-0358-9 · Cited by 172
“Consistent with this observation, deficiency of Abca1 exacerbates amyloidogenesis while overexpression of ABCA1 reduced the amyloid load in PDAPP transgenic mice [124].”
BackgroundMedeiros, R., Kitazawa, M., Passos, G. F., Baglietto-Vargas, D., Cheng, D., Cribbs, D. H., & LaFerla, F. M. (2013) · The American Journal of Pathology · doi:10.1016/j.ajpath.2013.01.051 · Cited by 163
ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes
Rawat, V., Wang, S., Sima, J., Bar, R., Liraz, O., Gundimeda, U., Parekh, T., Chan, J., Johansson, J. O., Tang, C., et al. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.1400-19.2019 · Cited by 165
“Furthermore, overexpressing ABCA1 increases the percentage of lipidated ApoE fractions and reduces A accumulation (Wahrle et al., 2008).”
BackgroundYamazaki, Y., Painter, M. M., Bu, G., & Kanekiyo, T. (2016) · CNS Drugs · doi:10.1007/s40263-016-0361-4 · Cited by 173
Litvinchuk, A., Suh, J. H., Guo, J. L., Lin, K., Davis, S. S., Bien-Ly, N., Tycksen, E., Tabor, G. T., Remolina Serrano, J., Manis, M., et al. (2024) · Neuron · doi:10.1016/j.neuron.2023.10.023 · Cited by 161
Self-citationInsulin resistance and pathological brain ageing
Cholerton, B., Baker, L. D., & Craft, S. (2011) · Diabetic Medicine · doi:10.1111/j.1464-5491.2011.03464.x · Cited by 164
Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease
Yao, J., Ho, D. J., Calingasan, N. Y., Pipalia, N. H., Lin, M. T. S., & Beal, M. F. (2012) · The Journal of Experimental Medicine · doi:10.1084/jem.20121239 · Cited by 162
“Notably, ABCA1 is involved not only in cholesterol efflux, but also in increasing ApoE lipidation and improving A clearance (Hirsch-Reinshagen et al., 2005; Koldamova et al., 2005a; Wahrle et al., 2005, 2008; Cramer et al., 2012).”
BackgroundThe Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease
Jacobo‐Albavera, L., Domínguez‐Pérez, M., Medina-Leyte, D. J., González-Garrido, A., & Villarreal-Molina, M. T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041593 · Cited by 172
More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration
Lane-Donovan, C., Philips, G. T., & Herz, J. (2014) · Neuron · doi:10.1016/j.neuron.2014.08.005 · Cited by 158
“Overexpression of ABCA1 increases ApoE lipidation and reduces amyloid deposition in a mouse model of AD (Wahrle et al., 2008); conversely, decreasing ABCA1 expression has the opposite effect (Wahrle et al., 2005).”
Diet Intervention and Cerebrospinal Fluid Biomarkers in Amnestic Mild Cognitive Impairment
Bayer-Carter, J. L., Green, P. S., Montine, T. J., VanFossen, B. T., Baker, L. D., Watson, G. S., Bonner, L. M., Callaghan, M., Leverenz, J. B., Walter, B. K., et al. (2011) · Archives of Neurology · doi:10.1001/archneurol.2011.125 · Cited by 160
“Next, we examined diet effects on CSF APOE because of its important role in A clearance.(31,32) Concentrations of APOE were increased by the LOW diet and decreased by the HIGH diet (Figure 2C; time diet interaction, P=.”
Mammalian P4-ATPases and ABC transporters and their role in phospholipid transport
Coleman, J. A., Quazi, F., & Molday, R. S. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2012.10.006 · Cited by 160
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
Karasinska, J. M., Rinninger, F., Lütjohann, D., Ruddle, P., Franciosi, S., Kruit, J. K., Singaraja, R. R., Hirsch-Reinshagen, V., Fan, J., Brunham, L. R., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.4741-08.2009 · Cited by 133
“These data, in addition to the reports suggesting that overexpression of ABCA1 in the brain decreases amyloid deposition (Wahrle et al., 2008) and improves neuronal function (Jiang et al., 2008), all point to significant disturbances in CNS cholesterol homeostasis that may be influenced at least in…”
ResultSelf-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
Kim, J., Yoon, H., Basak, J., & Kim, J. (2014) · Molecules and Cells · doi:10.14348/molcells.2014.0248 · Cited by 141
“ATP-binding cassette transporter A1 (ABCA1) overexpression in APP transgenic mice also showed a similar phenotype (Wahrle et al., 2008).”
BackgroundSelf-citationHuynh, T.-P. V., Wang, C., Tran, A. C., Tabor, G. T., Mahan, T. E., Francis, C. M., Finn, M. B., Spellman, R., Manis, M., Tanzi, R. E., et al. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0337-1 · Cited by 139
Self-citationFitz, N. F., Cronican, A. A., Saleem, M., Fauq, A. H., Chapman, R., Lefterov, I., & Koldamova, R. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.1937-12.2012 · Cited by 119
“In contrast, it has been shown that transgenic overexpression of ABCA1 (Wahrle et al., 2008) or treatments with liver X receptor (LXR) and retinoid X receptor (RXR) agonists (Koldamova et al.”
BackgroundLoss‐of‐function mutation in ABCA1 and risk of Alzheimer's disease and cerebrovascular disease
Nordestgaard, L. T., Tybjærg‐Hansen, A., Nordestgaard, B. G., & Frikke‐Schmidt, R. (2015) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2015.04.006 · Cited by 139
“overexpression of ABCA1 increases lipidation of apoE– containing lipoproteins and decreases the amyloid burden [33].”
Role of ABC Transporters in the Pathogenesis of Alzheimer’s Disease
Abuznait, A. H., & Kaddoumi, A. (2012) · ACS Chemical Neuroscience · doi:10.1021/cn300077c · Cited by 145
ATP‐binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro
Chan, S. L., Kim, W. S., Kwok, J. B., Hill, A. F., Cappai, R., Rye, K., & Garner, B. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05433.x · Cited by 135
The genetic landscape of Alzheimer disease
Carmona, S., Hardy, J., & Guerreiro, R. J. (2018) · Handbook of clinical neurology · doi:10.1016/b978-0-444-64076-5.00026-0 · Cited by 140
In 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
“ApoE particles in the CSF or secreted by cultured astrocytes are a heterogeneous mixture that vary in size depending upon the degree of lipidation [5,18-20].”
BackgroundSelf-citationValenza, M., Marullo, M., Di Paolo, E., Cesana, E., Zuccato, C., Biella, G., & Cattaneo, E. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2014.162 · Cited by 133
“level in the GCM (GCMR6/2ABCA1) compared with GCMR6/2pcDNA (Figure 3f, left), in agreement with the evidence that greater than sixfold overexpression of ABCA1 in the mouse brain is required to alter apoE levels.(22)”
ResultATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing
Satoh, K., Abe-Dohmae, S., Yokoyama, S., St George-Hyslop, P., & Fraser, P. E. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.655076 · Cited by 128
microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain
Kim, J., Yoon, H., Horie, T., Burchett, J. M., Restivo, J. L., Rotllan, N., Ramírez, C. M., Verghese, P. B., Ihara, M., Hoe, H.-S., et al. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2053-15.2015 · Cited by 128
“Moreover, animal studies have demonstrated that ABCA1 levels regulate A deposition in vivo (HirschReinshagen et al., 2004; Wahrle et al., 2004, 2005, 2008; Koldamova et al., 2005).”
BackgroundResultSelf-citationNuclear receptors as therapeutic targets for Alzheimer's disease
Mandrekar-Colucci, S., & Landreth, G. E. (2011) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2011.594043 · Cited by 126
“Conversely, overexpression of ABCA1 in a mouse model of AD was shown to decrease both soluble and fibrillar pools of Ab in 12-month-old mice and reduce plaque burden [53].”
BackgroundMarzolo, M.-P., & Bu, G. (2009) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2008.10.005 · Cited by 122
Investigational ABC transporter inhibitors
Falasca, M., & Linton, K. J. (2012) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2012.679339 · Cited by 126
“Mutations in ABCA1 have been linked to Tangier disease [10] and overexpression of the gene has been shown to be protective in a mouse model of Alzheimer’s disease [11], while mutations in ABCA3 and ABCA7 are linked to Neonatal surfactant deficiency [12] and Sjogren syndrome [13], respectively.”
BackgroundABC Transporters and Drug Efflux at the Blood-Brain Barrier
Shen, S., & Zhang, W. (2010) · Reviews in the Neurosciences · doi:10.1515/revneuro.2010.21.1.29 · Cited by 120
Role of Cholesterol in APP Metabolism and Its Significance in Alzheimer’s Disease Pathogenesis
Maulik, M., Westaway, D. A., Jhamandas, J. H., & Kar, S. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8337-y · Cited by 121
The vascular contribution to Alzheimer's disease
Altman, R., & Rutledge, J. C. (2010) · Clinical Science · doi:10.1042/cs20100094 · Cited by 93
ACAT1/SOAT1 as a Therapeutic Target for Alzheimer's Disease
Shibuya, Y., Chang, C. C., & Chang, T.-Y. (2015) · Future Medicinal Chemistry · doi:10.4155/fmc.15.161 · Cited by 113
Grimm, M. O. W., Michaelson, D. M., & Hartmann, T. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r076331 · Cited by 114
“Beneficial effects of ABCA1 activation were also observed in the PDAPP mouse model where amyloid deposition was reduced by overexpression of ABCA1 (52).”
BackgroundAPOE3 -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia
Liu, C.-C., Murray, M. E., Li, X., Zhao, N., Wang, N., Heckman, M. G., Shue, F., Martens, Y., Li, Y., Raulin, A.-C., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abc9375 · Cited by 108
ElAli, A., & Rivest, S. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00045 · Cited by 115
“Interestingly, it was reported that PDAPP/abca1 transgenic mice that overexpress ABCA1, have reduced Aβ deposits in brain parenchyma compared to their littermates, and almost complete absence of vascular Aβ deposits (Wahrle et al., 2008), outlining an efficient elimination of Aβ across the NVU.”
BackgroundCyclodextrins, Blood–Brain Barrier, and Treatment of Neurological Diseases
Vecsernyés, M., Fenyvesi, F., Bácskay, I., Deli, M. A., Szente, L., & Fenyvesi, É. (2014) · Archives of Medical Research · doi:10.1016/j.arcmed.2014.11.020 · Cited by 102
ABC Transporters and the Alzheimer’s Disease Enigma
Wolf, A. M., Bauer, B., & Hartz, A. M. S. (2012) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2012.00054 · Cited by 109
“However, this approach is still in its infancy, and future research needs to address, amongst others, the following basic questions: (1) Do ABC transporters contribute to AD, and if so, what is the contribution of each transporter? membrane of the brain capillary endothelium; this step is facilitated by LRP1.”
BackgroundInfluentialImpact of Apolipoprotein E on Alzheimer’s Disease
Hauser, P. S., & Ryan, R. O. (2013) · Current Alzheimer Research · doi:10.2174/15672050113109990156 · Cited by 103
“In so doing, associated Aβ will be cleared via LDLR family members and degraded [64].”
BackgroundResultInteractions between inflammation, sex steroids, and Alzheimer’s disease risk factors
Uchoa, M. F., Moser, V. A., & Pike, C. J. (2016) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2016.09.001 · Cited by 105
“Thus, counteracting apoE4 effects by increasing apoE levels or lipidation status has been shown to ameliorate AD pathology in several mouse models of AD (Cramer et al., 2012; Jiang et al., 2008a; Wahrle et al., 2008).”
Apolipoprotein E, amyloid-beta, and neuroinflammation in Alzheimer’s disease
Dorey, E., Chang, N., Liu, Q. Y., Yang, Z., & Zhang, W. (2014) · Neuroscience Bulletin · doi:10.1007/s12264-013-1422-z · Cited by 105
“Nevertheless, one study demonstrated that over-expression of ABCA1 provides protection against amyloid deposition([52]).”
Animal models of dementia and cognitive dysfunction
Neha, N., Sodhi, R. K., Jaggi, A. S., & Singh, N. (2014) · Life Sciences · doi:10.1016/j.lfs.2014.05.017 · Cited by 104
High-Density Lipoproteins and Cerebrovascular Integrity in Alzheimer’s Disease
Stukas, S. K., Robert, J., & Wellington, C. L. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.01.003 · Cited by 101
Self-citationABCA7 Mediates Phagocytic Clearance of Amyloid-β in the Brain
Fu, Y., Hsiao, J.-H. T., Paxinos, G., Halliday, G. M., & Kim, W. S. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160456 · Cited by 99
“ABCA1 also modulates amyloid-(cid:2) secretion and deposition [9–14].”
Gosselet, F., Candela, P., Sevin, E., Bérézowski, V., Cecchelli, R., & Fénart, L. (2008) · Brain Research · doi:10.1016/j.brainres.2008.10.036 · Cited by 110
“In transgenic mice, ABCA1 deficiency promotes amyloidogenesis (Hirsch-Reinshagen et al., 2005; Koldamova et al., 2005a; Wahrle et al., 2005) while ABCA1 overexpression reduces amyloid deposition probably through ApoE expression and lipidation (Wahrle et al., 2008).”
BackgroundLipid metabolism and neuroinflammation in Alzheimer’s disease: a role for liver X receptors
Kang, J., & Rivest, S. (2012) · Endocrine Reviews · doi:10.1210/er.2011-1049 · Cited by 94
Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo
Tai, L. M., Koster, K. P., Luo, J., Lee, S. H., Wang, Y.-T., Collins, N. C., Ben Aissa, M., Thatcher, G. R. J., & LaDu, M. J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.600833 · Cited by 89
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 94
“In line with this, Abca1 deficiencyconsiderablyreducesthelevels of soluble apoE and its lipidation in AD mouse models, causing increased amyloid deposition in the brain parenchyma and microvasculature [76, 77], whereas its overexpression produces the opposite effects [78].”
Medeiros, R., Kitazawa, M., Chabrier, M. A., Cheng, D., Baglietto‐Vargas, D., Kling, A., Möller, A., Green, K. N., & LaFerla, F. M. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.04.020 · Cited by 92
“Although deletion of ABCA1 increases the A deposition, its overexpression has an opposite effect through the increase in A clearance, in the PDAPP mice.(22,23) ABCA1 expression is highly regulated, on both transcriptional and posttranscriptional levels.”
BackgroundStukas, S. K., Robert, J., Lee, M., Kulić, I., Carr, M., Tourigny, K., Fan, J., Namjoshi, D., Lemke, K., DeValle, N., et al. (2014) · Journal of the American Heart Association · doi:10.1161/jaha.114.001156 · Cited by 96
“In contrast, brain-selective overexpression of ABCA1 in PDAPP mice does not alter CNS apoE or apoA-I levels.(16) Finally, treatment of APP/PS1 mice with”
BackgroundSelf-citation
Metadata
- Authors
- Wahrle, S. E., Jiang, H., Parsadanian, M., Kim, J., Li, A., Knoten, A., Jain, S., Hirsch-Reinshagen, V., Wellington, C. L., Bales, K. R., Paul, S. M., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- University of British Columbia (CA)
- Eli Lilly (United States) (US)
- Corresponding author
- Holtzman, David M.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2008-01-17
- Volume
- 118
- Issue
- 2
- Pages
- 671-82
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2200302
- OpenAlex
- W2165895874
- Semantic Scholar
- d3897f2ef12c640d78228188112f4cc8ebffe747
- Cited by
- 370
- References
- 65
- Citations by year
- 2026: 4 · 2025: 15 · 2024: 16 · 2023: 15 · 2022: 20 · 2021: 24 · 2020: 22 · 2019: 17 · 2018: 13 · 2017: 20 · 2016: 14 · 2015: 24 · 2014: 33 · 2013: 25 · 2012: 30
- FWCI
- 15.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Funders
- American Health Assistance Foundation
- Eli Lilly and Company
- National Institutes of Health (AG13956)
- Canadian Institutes of Health Research
- National Institute on Aging (R01 AG013956, R37AG013956, AG13956)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK079333)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD047396, K08 HD047396)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- ABCA1, Alzheimer's disease, amyloid-beta deposition, amyloid plaques, apolipoprotein E, amyloid precursor protein overexpression, transgenic mice, dentate gyrus, cerebrospinal fluid, astrocytes, APOE genotype, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Astrocytes, Brain, Brain Chemistry, Disease Models, Animal, Lipoproteins, Male, Mice, Transgenic, Amyloid beta-Peptides, ATP-Binding Cassette Transporters, Mice, ATP Binding Cassette Transporter 1
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