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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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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
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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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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 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.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“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.
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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.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“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.
Strength:plain· not yet calibratedn = 5Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe 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
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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.
Strength:plain· not yet calibratedn = 5Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- It may state two separate claims as one. 16
- Probably not a substantial claim. 4
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 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.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 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.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not matched
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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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Not matched
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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.
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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.
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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.
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
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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.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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.
Three-month cortical Aβ40 total does not equal its components
MinorFor the line D transgenic group, carbonate Aβ40 of 0.23 plus guanidine Aβ40 of 0.05 gives 0.28, not the reported total of 0.73.
Reported 0.73 · recomputed 0.28
“| +, 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 |”
Citations
Cites
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Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1
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Items 201–300 of 372
Sodhi, R. K., Singh, N., & Jaggi, A. S. (2011) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-011-0654-6 · Cited by 36
“The several genes linked with lipid homeostasis such as Apoe, Lrp1, Abca1, Lxr and Cyp46 are related with AD (Wahrle et al. 2005, 2008).”
BackgroundGuimaraes, M. E. N., Lopez-Blanco, R., Correa, J., Fernandez‐Villamarin, M., Millón, M. B. B., Adami, P. V. M., Morelli, L., Kumar, V., Wempe, M. F., Cuello, A. C., et al. (2021) · ACS Nano · doi:10.1021/acsnano.0c09159 · Cited by 36
Some Candidate Drugs for Pharmacotherapy of Alzheimer’s Disease
Miziak, B., Błaszczyk, B., & Czuczwar, S. J. (2021) · Pharmaceuticals · doi:10.3390/ph14050458 · Cited by 35
The Pathological Effects of Circulating Hydrophobic Bile Acids in Alzheimer’s Disease
Ehtezazi, T., Rahman, K., Davies, R., & Leach, A. G. (2023) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-220071 · Cited by 37
“In fact, overexpressing ABCA1 increased lipidation of apoE in the CNS and reduced amyloid burden [229].”
BackgroundValkenburgh, J. S. V., Meuret, C. J., Martinez, A. E., Kodancha, V., Solomon, V. A., Chen, K., & Yassine, H. N. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.700847 · Cited by 38
Oxysterols and the NeuroVascular Unit (NVU): A far true love with bright and dark sides
Saint‐Pol, J., & Gosselet, F. (2019) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2019.04.017 · Cited by 33
Peripheral cholesterol metabolic disorders and Alzheimer s disease
Ledesma, M. D. (2012) · Frontiers in Bioscience-Elite · doi:10.2741/e368 · Cited by 33
Mullane, K., & Williams, M. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.09.027 · Cited by 32
Emerging Role of ABC Transporters in Glia Cells in Health and Diseases of the Central Nervous System
Villa, M., Wu, J., Hansen, S. M., & Pahnke, J. (2024) · Cells · doi:10.3390/cells13090740 · Cited by 43
“Wahrle et al. investigated the potential therapeutic role of targeting ABCA1 in AD [183].”
BackgroundInfluentialPahnke, J., Fröhlich, C., Krohn, M., Schumacher, T., & Paarmann, K. (2013) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2013.08.007 · Cited by 35
“…formation indirectly via facilitation of apoE lipidation; specifically, the binding of apoE-lipid particles with Aβ facilitates the cellular uptake and clearance of Aβ via the ApoE-receptor LRP1 (Bell et al., 2007; HirschReinshagen et al., 2009; Hirsch-Reinshagen et al., 2007; Wahrle et al., 2008).”
BackgroundYang, D.-S., Stavrides, P. H., Kumar, A. R., Jiang, Y., Mohan, P. S., Ohno, M., Dobrenis, K., Davidson, C. D., Saito, M., Pawlik, M., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx001 · Cited by 33
Khatib, T., Chisholm, D. R., Whiting, A., Platt, B., & McCaffery, P. J. A. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190931 · Cited by 31
Puris, E., Auriola, S. O. K., Petralla, S., Hartman, R., Gynther, M., de Lange, E. C. M., & Fricker, G. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105741 · Cited by 30
“NQ - not quantified, as not investigated in the study; ULQ - under limit of quantification. a Abcg2, Abca1, OATP1A4 protein expression levels were quantified in the brain cortical tissue of WT (n = 13 – Abcg2; n = 10 – Abca1; n = 6 – OATP1A4) and TgF344-AD (n = 11 – Abcg2; n = 11 – Abca1; n = 6 - OATP1A4) rats.”
BackgroundInfluentialMapping ApoE/Aβ binding regions to guide inhibitor discovery
Liu, Q. R., Wu, W., Fang, C.-L., Li, R., Liu, P., Lei, P., Hu, J., Sun, X., Zheng, Y.-Z., Zhao, Y., et al. (2011) · Molecular BioSystems · doi:10.1039/c1mb05019b · Cited by 29
Suon, S., Zhao, J. J., Villarreal, S. A., Anumula, N., Liu, M., Carangia, L. M., Renger, J. J., & Zerbinatti, C. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-44 · Cited by 31
“Correspondingly with LXR agonist treatment, a 6-fold genetic overexpression of ABCA1 in the brain led to a striking decrease of amyloid burden in APP-Tg mice [45].”
BackgroundDubnov, S., Bennett, E. R., Yayon, N., Yakov, O., Bennett, D. A., Seshadri, S. S., Mufson, E. J., Tzur, Y., Greenberg, D., Kuro‐o, M., et al. (2024) · Communications Biology · doi:10.1038/s42003-024-06407-y · Cited by 31
Zeng, B., Zhao, G., & Liu, H. L. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.01.005 · Cited by 30
Legleiter, J. A., Fryer, J. D., Holtzman, D. M., & Kowalewski, T. (2011) · ACS Chemical Neuroscience · doi:10.1021/cn2000475 · Cited by 28
Self-citationThe role of the ATP-Binding Cassette A1 (ABCA1) in neurological disorders: a mechanistic review
Paseban, T., Alavi, M. S., Etemad, L., & Roohbakhsh, A. (2023) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2023.2235718 · Cited by 32
“Similar with Wahrle study [83], overexpression of ABCA1, but not LRP-1, restored”
BackgroundInfluentialEffect of the ABCA1 agonist CS-6253 on amyloid-β and lipoprotein metabolism in cynomolgus monkeys
Noveir, S. D., Kerman, B. E., Xian, H., Meuret, C. J., Smadi, S., Martinez, A. E., Johansson, J., Zetterberg, H., Parks, B. A., Kuklenyik, Z., et al. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01028-1 · Cited by 30
“ATP binding cassette 1 (ABCA1) participates in the formation of nascent HDL particles [12] and in the clearance of Aβ from the brain [13].”
BackgroundBasak, J. M., Kim, J., Pyatkivskyy, Y., Wildsmith, K. R., Jiang, H., Parsadanian, M., Patterson, B. W., Bateman, R. J., & Holtzman, D. M. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-14 · Cited by 27
“One proposed mechanism is ABCA1 levels could alter Aβ clearance from the brain [30,43]; however this hypothesis has never been tested in vivo.”
BackgroundMethodInfluentialSelf-citationABCA1 Deficiency Affects Basal Cognitive Deficits and Dendritic Density in Mice
Fitz, N. F., Carter, A. Y., Tapias, V., Castranio, E. L., Kodali, R. B., Lefterov, I. M., & Koldamova, R. P. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161056 · Cited by 27
“In contrast, Abca1 overexpression in PDAPP mice decreases amyloid burden [11].”
New Genes and New Insights from Old Genes
Ringman, J. M., & Coppola, G. (2013) · CONTINUUM Lifelong Learning in Neurology · doi:10.1212/01.con.0000429179.21977.a1 · Cited by 27
“Lipidation of particles containing ApoE may be required for amyloid clearance, as mice devoid of the ATP binding cassette 1 (ABCA1), which lipidates ApoE, show increased amyloid deposition,(50) and overexpression of ABCA1 reduces amyloid deposition.(51) Microdialysis experiments in transgenic mice suggest that ApoE is…”
BackgroundPeripheral cholesterol metabolic disorders and Alzheimer s disease
Maria, D. L. (2011) · Frontiers in Bioscience-Elite · doi:10.2741/368 · Cited by 35
“Overexpression of ABCA1 reduces Aβ deposition in AD mouse models (134) and association of ABCA1 genetic variants have been made with risk for AD”
BackgroundCarter, A. Y., Letronne, F., Fitz, N. F., Mounier, A., Wolfe, C. M., Nam, K. N., Reeves, V. L., Kamboh, H., Lefterov, I., & Koldamova, R. (2017) · PLOS ONE · doi:10.1371/journal.pone.0172161 · Cited by 28
Axl receptor tyrosine kinase is a regulator of apolipoprotein E
Zhao, W., Fan, J., Kulic, I., Koh, C., Clark, A., Meuller, J., Engkvist, O., Barichievy, S., Raynoschek, C., Hicks, R., et al. (2020) · Molecular Brain · doi:10.1186/s13041-020-00609-1 · Cited by 25
Self-citationPahnke, J., Bascuñana, P., Brackhan, M., Stefan, K., Namasivayam, V., Koldamova, R. P., Wu, J., Möhle, L., & Stefan, S. M. (2021) · Free Neuropathology · doi:10.17879/freeneuropathology-2021-3528 · Cited by 29
APOE4 is a Risk Factor and Potential Therapeutic Target for Alzheimer's Disease
Ayyubova, G. (2023) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527322666230303114425 · Cited by 23
Koudinov, A. R., Kezlya, E., Koudinova, N. V., & Berezov, T. T. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1202 · Cited by 25
“However, there is still a definite tendency towards utilizing the structural associations of ApoE with A β as a major explanation for the role of ApoE in neurodegeneration, with recent research by Wahrle et al. being an example [58].”
Calpain Inhibition as a Potential Treatment of Alzheimer's Disease
Getz, G. S. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.04.027 · Cited by 25
High-density lipoprotein-related cholesterol metabolism in Alzheimer's disease
Pedrini, S., Chatterjee, P., Hone, E., & Martins, R. N. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15170 · Cited by 22
Identification of a Chrysanthemic Ester as an Apolipoprotein E Inducer in Astrocytes
Fan, J., Zareyan, S., Zhao, W., Shimizu, Y., Pfeifer, T. A., Tak, J., Isman, M. B., den Hoven, B. G. V., Duggan, M. E., Wood, M. W., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0162384 · Cited by 24
Self-citationWang, L., Liu, W., Fan, Y., Liu, T., & Yu, C. (2017) · Europe PMC (PubMed Central) · doi:10.22038/ijbms.2017.8669 · Cited by 24
Research progress of the CXCR4 mechanism in Alzheimer's disease
Wang, Q., Fang, C., Huang, X., & Xue, L. (2022) · Ibrain · doi:10.1002/ibra.12026 · Cited by 24
“30 Wahrle et al. 31 used a PDAPP transgenic AD mouse model and found that the ABCA1 deletion led to increased A β peptide deposition and overexpression of ABCA1 inhibited A β deposition.”
Induction of Alzheimer’s-like changes in brain of mice expressing mutant APP fed excess methionine
McCampbell, A., Wessner, K., Marlatt, M. W., Wolffe, C., Toolan, D. M., Podtelezhnikov, A. A., Yeh, S., Zhang, R., Szczerba, P., Tanis, K. Q., et al. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.07087.x · Cited by 24
MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease
Yoon, H., Flores, L. F., & Kim, J. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2016.04.020 · Cited by 23
“ABC transporter protein families regulate Aβ production and secretion in vitro [62-69].”
BackgroundResultSelf-citationStukas, S. K., May, S., Wilkinson, A., Chan, J. Y., Donkin, J. J., & Wellington, C. L. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2011.08.014 · Cited by 23
Self-citationSwaminathan, S. K., Zhou, A. L., Ahlschwede, K. M., Curran, G. L., Lowe, V. J., Li, L., & Kandimalla, K. K. (2020) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.120.265876 · Cited by 25
“Studies have shown that ABCA1 overexpression mitigates, whereas ABCA1 deletion exacerbates, brain A b deposition in AD mice (Wahrle et al., 2005, 2008).”
BackgroundFan, J., Stukas, S., Wong, C., Chan, J., May, S., DeValle, N., Hirsch-Reinshagen, V., Wilkinson, A., Oda, M. N., & Wellington, C. L. (2011) · Journal of Lipid Research · doi:10.1194/jlr.m014365 · Cited by 21
“apoE that exacerbates the formation of amyloid plaques [25-27], whereas selective overexpression of ABCA1 by 6-fold of more results in lipid-enriched apoE that inhibits amyloiodogenesis [28].”
BackgroundSelf-citationKontush, A., & Chapman, M. J. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.169714 · Cited by 22
Valencia-Olvera, A. C., Balu, D., Faulk, N., Amiridis, A., Wang, Y., Pham, C., Avila-Munoz, E., York, J. M., Thatcher, G. R. J., & LaDu, M. J. (2023) · Neurotherapeutics · doi:10.1007/s13311-023-01375-3 · Cited by 22
Lipoprotein Particles in Cerebrospinal Fluid
Tsujita, M., Melchior, J. T., & Yokoyama, S. (2024) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.123.318284 · Cited by 24
Contributions of Drug Transporters to Blood-Brain Barriers
Liu, L., & Liu, X. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-7647-4_9 · Cited by 21
Lim, F. T., Lim, S. M., & Ramasamy, K. (2017) · Food & Function · doi:10.1039/c7fo00764g · Cited by 21
Dwomoh, L., Rossi, M., Scarpa, M., Khajehali, E., Molloy, C., Herzyk, P., Mistry, S. N., Bottrill, A. R., Sexton, P. M., Christopoulos, A., et al. (2022) · Science Signaling · doi:10.1126/scisignal.abm3720 · Cited by 23
“3C).”
Huang, H. X., Inglese, P., Tang, J., Yagoubi, R., Correia, G. D. S., der Sluis, V. M. H.-V., Camuzeaux, S., Wu, V., Kopanitsa, M. V., Willumsen, N., et al. (2024) · Journal of Neurochemistry · doi:10.1111/jnc.16042 · Cited by 22
Derk, J., Bermudez‐Hernandez, K., Rodriguez, M., He, M., Koh, H., Abedini, A., Li, H., Fenyö, D., & Schmidt, A. M. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180088 · Cited by 21
“Second,subse-quentanalysesofmutationswithinanimalmodelshas illuminated major players from the innate immune system that increase or decrease AD progression, such as CCR2, CX3CR1, complement components, and CXCL8 and the previously mentioned lipid handlers [26–28].”
Loiola, R. A., Nguyen, C., Dib, S., Saint-Pol, J., Dehouck, L., Sevin, E., Naudot, M., Landry, C., Pahnke, J., Pot, C., et al. (2024) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2024.167479 · Cited by 20
Alzheimer’s disease and age-related macular degeneration: Shared and distinct immune mechanisms
Butovsky, O., & Rosenzweig, N. (2025) · Immunity · doi:10.1016/j.immuni.2025.04.013 · Cited by 22
O'Callaghan, P. W., Noborn, F., Sehlin, D., Li, J., Lannfelt, L., Lindahl, U., & Zhang, X. (2014) · Amyloid · doi:10.3109/13506129.2013.879643 · Cited by 20
Potential Therapeutic Implications of Gelsolin in Alzheimer's Disease
Ji, L., Zhao, X., & Hua, Z. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-141548 · Cited by 20
“However, overexpressed ABCA1 increased ApoE lipidation and decreased amyloid deposition [71].”
Hormonal modulators of glial ABCA1 and apoE levels
Fan, J., Shimizu, Y., Chan, J. Y., Wilkinson, A., Ito, A., Tontonoz, P., Dullaghan, E. M., Galea, L. A. M., Pfeifer, T. A., & Wellington, C. L. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m042473 · Cited by 20
Self-citationBhat, N. R. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-150098 · Cited by 18
“, LXR, PPARs) that regulate their synthesis also influence cognitive function in AD models [86–89].”
Zinc affects the proteolytic stability of Apolipoprotein E in an isoform-dependent way
Xu, H. J., Gupta, V. B., Martins, I. J., Martins, R. N., Fowler, C. J., Bush, A. I., Finkelstein, D. I., & Adlard, P. A. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.06.016 · Cited by 20
“ApoE receptors and the ATP binding cassette A1 (ABCA1) have also been found to influence ApoE levels in the brain (44-48).”
Tansley, G., Holmes, D. T., Lütjohann, D., Head, E., & Wellington, C. L. (2012) · Current Gerontology and Geriatrics Research · doi:10.1155/2012/179318 · Cited by 19
Self-citationJasmin, S. B., Pearson, V., Lalonde, D., Domenger, D., Théroux, L., & Poirier, J. (2014) · Brain Research · doi:10.1016/j.brainres.2014.03.016 · Cited by 19
“3) and, supports previous works showing a functional biological interaction between glial ABCA1 and apoE secretion during lipoprotein lipidation (Hirsch-Reinshagen et al., 2004; Wahrle et al., 2008, 2004).”
Cai, R., Han, J., Sun, J. L., Huang, R., Tian, S., Shen, Y., & Wang, S. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00257 · Cited by 17
“Recently, a few studies suggested the important role of ABCA1 on the pathology of AD (Koldamova et al., 2005; Wahrle et al., 2008; Elali and Rivest, 2013).”
BackgroundDefective Lysosomal Lipid Catabolism as a Common Pathogenic Mechanism for Dementia
Lee, J. Y., Marian, O. C., & Don, A. S. (2021) · NeuroMolecular Medicine · doi:10.1007/s12017-021-08644-4 · Cited by 18
Tate, M., Wijeratne, H. R. S., Kim, B., Philtjens, S., You, Y., Lee, D., Gutierrez, D. A., Sharify, D., Wells, M., Perez‐Cardelo, M., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.14243 · Cited by 21
“13 Thus, it is a promising approach to identify therapeutic targets to increase ABCA1 expression and reduce amyloid pathology.”
Self-citationApolipoprotein E-mediated Modulation of ADAM10 in Alzheimer's Disease
Shackleton, B., Crawford, F., & Bachmeier, C. J. (2017) · Current Alzheimer Research · doi:10.2174/1567205014666170203093219 · Cited by 16
Rahimi, A., Sameei, P., Mousavi, S., Ghaderi, K., Hassani, A., Hassani, S., & Alipour, S. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04143-2 · Cited by 18
“Thus, while ABCA1 overexpression lowers Aβ deposition [80], genetic deletion of ABCA1 results in inadequate APOE lipidation and increased Aβ plaque burden [81].”
Reconstituted HDL: a therapy for atherosclerosis and beyond
Murphy, A. J., Chin-Dusting, J. P. F., & Sviridov, D. (2009) · Clinical Lipidology · doi:10.2217/clp.09.68 · Cited by 16
MicroRNA: a connecting road between apoptosis and cholesterol metabolism
Adlakha, Y. K., & Saini, N. (2016) · Tumor Biology · doi:10.1007/s13277-016-4988-z · Cited by 16
“Overexpression of ABCA1 dramatically reduces Aβ deposition as well as reduces the risk of atherosclerosis [197, 198].”
BackgroundValencia‐Olvera, A. C., Balu, D., Bellur, S., McNally, T. P., Saleh, Y., Pham, D., Ghura, S., York, J. M., Johansson, J. O., LaDu, M. J., et al. (2023) · Alzheimer s Research & Therapy · doi:10.1186/s13195-023-01353-z · Cited by 18
Lee, C.-Y., Riffle, D., Xiong, Y., Momtaz, N., Lei, Y., Pariser, J. M., Sikdar, D., Hwang, A., Duan, Z., & Zhang, J. (2024) · BMC Neuroscience · doi:10.1186/s12868-024-00867-y · Cited by 17
“Additionally, ABCA1 deficiency increases amyloid deposition in the brains of amyloid precursor protein (APP) transgenic mice [66, 67].”
BackgroundEhrenberg, A. J., Sant, C., Pereira, F. L., Li, S. H., Buxton, J., Langlois, S., Trinidad, M. I., Oh, I. M., Leite, R. E. P., Rodriguez, R. D., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70087 · Cited by 16
“DEG, differentially expressed gene; GSEA, gene set enrichment analysis; LC, locus coeruleus; RIN, RNA integrity number; SN, substantia nigra in A β metabolism and apoE lipidation, 38–40 and MYLIP is a selective E3 ubiquitin-protein ligase for LDLR, 41,42 making these three pro-teinsprioritiesforIHC.”
Thangavelu, B., Wilfred, B. R., Johnson, D., Gilsdorf, J. S., Shear, D. A., & Boutté, A. M. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00915 · Cited by 16
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Stepler, K. E., & Robinson, R. A. S. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-05542-4_1 · Cited by 15
APOE-Targeted Therapeutics for Alzheimer's Disease
Yassine, H. N., Hugo, C., O'Donovan, B., Stephens, I. O., Johnson, L. A., Cole, G., TCW, J., Johansson, J., Kisler, K., & Chiba-Falek, O. (2025) · The Journal of Neuroscience · doi:10.1523/jneurosci.1388-25.2025 · Cited by 20
Dib, S., Loiola, R. A., Sevin, E., Saint‐Pol, J., Shimizu, F., Kanda, T., Pahnke, J., & Gosselet, F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065992 · Cited by 15
Apolipoprotein ε in Brain and Retinal Neurodegenerative Diseases
Abyadeh, M., Gupta, V., Paulo, J. A., Sheriff, S., Shadfar, S., Fitzhenry, M. J., Amirkhani, A., Gupta, V. B., Salekdeh, G. H., Haynes, P. A., et al. (2023) · Aging and Disease · doi:10.14336/ad.2023.0312-1 · Cited by 15
“Interestingly increased ApoE lipidation in ABCA1 transgenic mice leads to decreased Aβ deposition and ABCA1 deletion resulted in increased brain Aβ and amyloid load[40, 115].”
Xia, P., Ma, H., Chen, J., Liu, Y., Cui, X., Wang, C., Zong, S., Wang, L., Liu, Y., & Lu, Z. (2023) · BMC Medical Genomics · doi:10.1186/s12920-023-01479-x · Cited by 14
Michaelis, M., Sobczak, A., Koczan, D., Langhammer, M., Reinsch, N., Schoen, J., & Weitzel, J. M. (2017) · BMC Genomics · doi:10.1186/s12864-017-4288-z · Cited by 13
Genetics and regulation of HDL metabolism
Kardassis, D., Thymiakou, E., & Chroni, A. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2021.159060 · Cited by 12
Domains of apoE4 required for the biogenesis of apoE-containing HDL
Vezeridis, A. M., Chroni, A., & Zannis, V. I. (2011) · Annals of Medicine · doi:10.3109/07853890.2010.549143 · Cited by 12
Xu, G., Yang, L., Guan, P.-P., Wang, Z., & Wang, P. (2019) · Neurotherapeutics · doi:10.1007/s13311-018-00704-1 · Cited by 12
Takamura, A., Kawarabayashi, T., Yokoseki, T., Shibata, M. S., Morishima‐Kawashima, M., Saito, Y., Murayama, S., Ihara, Y., Abe, K., Shoji, M., et al. (2011) · Journal of Neuroscience Research · doi:10.1002/jnr.22615 · Cited by 11
“In the case of HDL, a previous study showed that Ab depositions is enhanced in PDAPP transgenic mice under conditions of markedly suppressed HDL (Wahrle et al., 2005), whereas Ab depositions is inhibited in PDAPP transgenic mice under conditions of markedly overexpressed HDL (Wahrle et al., 2008).”
BackgroundCholesterol and oxysterols in retinal neuron-glia interactions: relevance for glaucoma
Masson, E., Serrano, J., Léger-Charnay, E., & Acar, N. (2024) · Frontiers in Ophthalmology · doi:10.3389/fopht.2023.1303649 · Cited by 12
“Moreover, experimental data obtained from manipulation of cholesterol metabolism in rodents also support a role of cholesterol in neurodegenerative diseases (23 – 25).”
BackgroundDiaz, J. R., Martá-Ariza, M., Khodadadi‐Jamayran, A., Heguy, A., Tsirigos, A., Pankiewicz, J. E., Sullivan, P. M., & Sadowski, M. J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.845291 · Cited by 11
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“Notably, amyloid plaques were almost completely absent in the PDAPP/Abca1 mouse model, suggesting that Abca1 could lessen the A (cid:2) load in mice with AD [40].”
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Pharmacokinetic properties of MH84, a γ-secretase modulator with PPARγ agonistic activity
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“Overexpression of ABCA1 protein reduces deposition of Aβ in AD mouse model [25].”
BackgroundLCAT deficiency does not impair amyloid metabolism in APP/PS1 mice
Stukas, S., Freeman, L., Lee, M., Wilkinson, A., Ossoli, A., Vaisman, B., Demosky, S., Chan, J., Hirsch-Reinshagen, V., Remaley, A. T., et al. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m049940 · Cited by 9
Self-citationLestaevel, P., Bensoussan, H., Racine, R., et al. (2011) · Comptes Rendus Biologies · doi:10.1016/j.crvi.2010.12.004 · Cited by 8
“The gene expression modulation of ABC A1 relates to the work of Wahrle et al. showing that an over-expression of ABC A1 protein decreases the precipitation of ßA peptides [26].”
MethodStrickland, M. R., Wang, Z., Golden, L. R., Wang, H., Lu, P., Ren, Y., Tabor, G. T., Zhao, N., Ulrich, J. D., Han, X., et al. (2026) · Journal of Lipid Research · doi:10.1016/j.jlr.2026.101000 · Cited by 8
Self-citationLoeffler, D. A. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1368200 · Cited by 10
Research Progress of Lipid Metabolism-Mediated Neuroinflammation in Alzheimer’s Disease
Shen, Y., Wang, X., Liu, X., Wang, G., Hou, X., & Zhou, X. (2025) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-025-01648-9 · Cited by 12
“This process is important for maintaining lipid homeostasis in the brain, and ABCA1 overexpression can decrease amyloid deposition and improve Aβ clearance(Wahrle et al. 2004, 2008).”
Unni, P. A., Pillai, G. G., & Sajithalulu, S. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119079 · Cited by 7
Frisardi, V. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-111568 · Cited by 7
“On the other hand, overexpression of ABCA1 increases ApoE lipidation in the CNS and decreases amyloid plaque formation [81].”
BackgroundSarlak, Z., Moazzami, M., Hosseini, S. R. A., & Gharakhanlou, R. (2019) · PubMed · doi:10.22038/ijbms.2018.32911.7860 · Cited by 7
“Both in vivo and in vitro studies have shown that the down-regulation of the ABCA1 expression reduces the APOE in the brain, the cerebrospinal fluid, and plasma, and increases the Aβ load of the brain (29-33), while the up-regulation of the ABCA1 expression leads to an increase in the lipidation of APOE and reduces th…”
BackgroundWu, D., Hu, Y., Song, M., & Li, G. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.634948 · Cited by 7
“Cumulatively, ABCA1-mediated ApoE lipidation is thought to be necessary for the efficient clearance of Aβ and the improvement of cognitive impairment (Wahrle et al., 2008; Corona et al., 2016; Fitz et al., 2017).”
BackgroundWang, Z., Zhang, Q., Lin, J.-R., Jabalameli, M. R., Mitra, J., Nguyen, N., & Zhang, Z. (2020) · doi:10.21203/rs.3.rs-31864/v1 · Cited by 7
SHARMA, A. K., Mannan, A., & Singh, T. G. (2025) · Metabolic Brain Disease · doi:10.1007/s11011-025-01642-6 · Cited by 7
“…efflux in macrophages and explores 1 3 absence of ABCA1 leads to increased amyloid accumula - tion and cognitive impairment in several APP transgenic mice, along with a significant reduction in soluble ApoE levels (Hirsch-Reinshagen et al. 2005; Wahrle et al. 2008 ; Lefterov et al. 2009 ).”
Unraveling APOE4: The dual role in CNS and peripheral inflammation in Alzheimer's disease
Li, X., Li, Z., Chen, H., Guo, H., Ge, Y., Dong, F., Zhang, F., & Zhang, F. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.115199 · Cited by 7
Recurrent Lobar Intracerebral Hemorrhage in Tangier Disease
Feng, W., Sidorov, E. V., Smith, K. M., & Selim, M. H. (2011) · Journal of Stroke and Cerebrovascular Diseases · doi:10.1016/j.jstrokecerebrovasdis.2011.10.009 · Cited by 6
APOE loss of function: A genetic shield against Alzheimer’s disease
Tate, M. D., Karahan, H., & Kim, J. (2024) · Neuron · doi:10.1016/j.neuron.2024.03.003 · Cited by 5
Self-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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