Deletion of Abca1 Increases Aβ Deposition in the PDAPP Transgenic Mouse Model of Alzheimer Disease
Open accessAbstract
Apolipoprotein E (apoE) genotype has a major influence on the risk for Alzheimer disease (AD). Different apoE isoforms may alter AD pathogenesis via their interactions with the amyloid beta-peptide (Abeta). Mice lacking the lipid transporter ABCA1 were found to have markedly decreased levels and lipidation of apoE in the central nervous system. We hypothesized that if Abca1-/- mice were bred to the PDAPP mouse model of AD, PDAPP Abca1-/ mice would have a phenotype similar to that of PDAPP Apoe+/- and PDAPP Apoe-/- mice, which develop less amyloid deposition than PDAPP Apoe+/+ mice. In contrast to this prediction, 12-month-old PDAPP Abca -/- mice had significantly higher levels of hippocampal Abeta, and cerebral amyloid angiopathy was significantly more common compared with PDAPP Abca1+/+ mice. Amyloid precursor protein (APP) C-terminal fragments were not different between Abca1 genotypes prior to plaque deposition in 3-month-old PDAPP mice, suggesting that deletion of Abca1 did not affect APP processing or Abeta production. As expected, 3-month-old PDAPP Abca1-/- mice had decreased apoE levels, but they also had a higher percentage of carbonate-insoluble apoE, suggesting that poorly lipidated apoE is less soluble in vivo. We also found that 12-month-old PDAPP Abca1-/- mice had a higher percentage of carbonate-insoluble apoE and that apoE deposits co-localize with amyloid plaques, demonstrating that poorly lipidated apoE co-deposits with insoluble Abeta. Together, these data suggest that despite substantially lower apoE levels, poorly lipidated apoE produced in the absence of ABCA1 is strongly amyloidogenic in vivo.
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ABCA1-mediated lipidation of apoE modulates amyloid plaque formation.
“In support of this possibility, it was recently demonstrated that ATP-binding cassette transporter A1 (ABCA1)-mediated lipidation of apoE modulates amyloid plaque formation (Hirsch-Reinshagen et al., 2005; Koldamova et al., 2005; Wahrle et al., 2005; Wahrle et al., 2008).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Wahrle et al., 2005
The Discussion reports that loss of ABCA1 increased amyloid deposition in PDAPP mice and identifies poorly lipidated apoE as the likely mechanism. But it says the proposed effect of increasing ABCA1 through apoE lipidation needs to be tested directly, so the citation overstates the mechanistic link as demonstrated. (LLM, conf=0.86)
Experimental — accuracy not yet measuredKnocking out Abca1 in amyloidosis mouse models increases the formation of Aβ peptides and amyloid plaque deposition.
“Interestingly, several studies have shown that knocking out Abca1 in amyloidosis mouse models increases the formation of Aβ peptides and amyloid plaque deposition. 11 , 12”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [12]
The Results report higher insoluble Aβ levels in 12-month-old PDAPP Abca1-knockout mice, and the Discussion concludes that Abca1 deletion increased amyloid deposition. But the Discussion says unchanged APP and APP-fragment levels before deposition suggest that Abca1 deletion does not increase Aβ production. The claim conflates increased deposition with increased formation of Aβ peptides. (LLM, conf=0.91)
Experimental — accuracy not yet measuredABCA1 overexpression or LXR/RXR agonist treatment decreases amyloid deposition in APP transgenic mouse models.
“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 [68]
The Discussion reports that an LXR agonist lowered brain Aβ40 and Aβ42 levels in APP23 mice before plaque deposition; it does not report decreased amyloid deposition from that treatment. It describes decreased deposition from increasing ABCA1 as a prediction that still needs direct testing, while this paper studied ABCA1 deletion. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOverexpression of ABCA1 reduces Aβ deposition in AD mouse models.
“Genetic studies with AD mouse models have demonstrated that the deletion of ABCA1 increases Aβ deposition, while overexpression of ABCA1 dramatically reduces Aβ deposition (Hirsch-Reinshagen et al., 2004; Koldamova et al., 2005; Wahrle et al., 2005; Wahrle et al., 2008; Wahrle et al., 2004).”
From miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression (2012) · cites this paper as Wahrle et al., 2005
The Discussion (page unavailable) predicts that increasing ABCA1 might decrease amyloid deposition, but explicitly says this hypothesis needs to be tested directly. The paper studies ABCA1 deletion, not overexpression, so it does not establish the claimed reduction or its magnitude. (LLM, conf=0.88)
Experimental — accuracy not yet measuredWe did not explore the lipidation status of different APOE isoforms, which influences Aβ pathology.
“Additionally, we did not explore the lipidation status of different APOE isoforms, which influences Aβ pathology (Koldamova et al, 2005; Wahrle et al, 2005).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Wahrle et al, 2005
The Discussion (page not provided) links poorly lipidated apoE to increased Aβ deposition in PDAPP mice and describes isoform-dependent interactions with Aβ in vitro. It does not directly show that the lipidation status of different human APOE isoforms influences Aβ pathology; it presents the mechanism for its mouse findings as likely rather than established. (LLM, conf=0.84)
Experimental — accuracy not yet measured
ABCA1 deletion did not have an effect on Aβ production.
“ABCA1 deletion did not have an effect on Aβ production (Koldamova et al., 2005; Wahrle et al., 2005), suggesting that the presence of poorly lipidated apoE somehow promotes the formation of amyloid fibrils.”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Wahrle et al., 2005
The Discussion reports no effect of Abca1 deletion on APP or APP C-terminal fragment levels before Aβ deposition and says this suggests ABCA1 does not influence Aβ production. The cited paper presents the production conclusion as an inference from those measurements, rather than an established absence of any effect. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDeletion of Abca1 and Lxr genes decreased apoE levels but increased or had no effect on Aβ deposition.
“Interestingly, deletion of ATP-binding cassette, sub-family A1 (Abca1) and liver x receptor (Lxr) genes decreased apoE levels but increased or had no effect on Aβ deposition (Hirsch-Reinshagen et al.,2005; Koldamova et al., 2005; Wahrle et al., 2005; Zelcer et al., 2007).”
From Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-β Amyloidosis (2011) · cites this paper as Wahrle et al., 2005
ABCA1 gene ablation in mice decreases APOE lipidation and levels and increases Aβ accumulation in APP transgenic mouse models.
“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 [68]
Modulation of ABCA1 affects Aβ levels and amyloid accumulation in vivo.
“We and others demonstrated that modulation of ABCA1 affects Aβ levels and amyloid accumulation in vivo.”
From miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression (2012) · cites this paper as Wahrle et al., 2005
ABCA1 deficiency leads to an increase in Aβ and amyloid deposition.
“ABCA1 deficiency leads to an increase in Aβ and amyloid deposition (Hirsch-Reinshagen et al., 2005; Koldamova et al., 2005; Wahrle et al., 2005)”
From miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression (2012) · cites this paper as Wahrle et al., 2005
Deletion of ABCA1 increases Aβ deposition in AD mouse models.
“Genetic studies with AD mouse models have demonstrated that the deletion of ABCA1 increases Aβ deposition, while overexpression of ABCA1 dramatically reduces Aβ deposition (Hirsch-Reinshagen et al., 2004; Koldamova et al., 2005; Wahrle et al., 2005; Wahrle et al., 2008; Wahrle et al., 2004).”
From miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression (2012) · cites this paper as Wahrle et al., 2005
The amyloid load in APP transgenic mice deficient in ABCA1 does not change, or even increases, when ABCA1−/− mice are crossed to various APP transgenic models.
“The amyloid load in APP transgenic mice deficient in ABCA1 did not change, or even increased, when ABCA1−/− mice were crossed to various APP transgenic models [40-42].”
From Measurement of apolipoprotein E and amyloid β clearance rates in the mouse brain using bolus stable isotope labeling (2012) · cites this paper as [42]
ABCA1 deficiency leads to an increase in both Aβ and amyloid load in the brains of three different transgenic APP mouse models.
“However, three independent studies demonstrated that ABCA1 deficiency leads to an increase in both Aβ and amyloid load in the brains of three different transgenic APP mouse models (Hirsch-Reinshagen et al., 2005; Koldamova et al., 2005; Wahrle et al., 2005).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Wahrle et al., 2005
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Self-citationHigh-density lipoprotein-related cholesterol metabolism in Alzheimer's disease
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“ABC transporter protein families regulate Aβ production and secretion in vitro [62-69].”
BackgroundResultTate, 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 16 · see citing works
“11,12 Conversely, increasing Abca1 expression,andsubsequentlyapoElipidation,reducesA β peptidesandplaque deposition.”
- Authors
- Wahrle, S. E., Jiang, H., Parsadanian, M., Hartman, R. E., Bales, K. R., Paul, S. M., & Holtzman, D. M.
- Affiliations
- Eli Lilly (United States) (US)
- Washington University in St. Louis (US)
- Corresponding author
- Holtzman, David M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-12
- Volume
- 280
- Issue
- 52
- Pages
- 43236-43242
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1991166529
- Cited by
- 325
- References
- 6
- Citations by year
- 2026: 2 · 2025: 12 · 2024: 14 · 2023: 16 · 2022: 12 · 2021: 17 · 2020: 15 · 2019: 15 · 2018: 10 · 2017: 15 · 2016: 11 · 2015: 21 · 2014: 18 · 2013: 20 · 2012: 26
- FWCI
- 8.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- National Institutes of Health (AG13956, AG11355)
- National Institute on Aging (AG11355, AG13956, P01AG011355)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- ABCA1, apolipoprotein E, amyloid-beta deposition, Alzheimer's disease, cerebral amyloid angiopathy, amyloid plaques, amyloidogenicity, hippocampus, APP processing
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Apolipoproteins E, Brain, Enzyme-Linked Immunosorbent Assay, Heterozygote, Hippocampus, Mice, Transgenic, Models, Genetic, Thiazoles, Time Factors, Blotting, Western, Amyloid beta-Peptides, Gene Deletion, Protein Structure, Tertiary, ATP-Binding Cassette Transporters, Mice, Benzothiazoles, ATP Binding Cassette Transporter 1
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