Deficiency of ABCA1 Impairs Apolipoprotein E Metabolism in Brain
Open accessAbstract
ABCA1 is a cholesterol transporter that is widely expressed throughout the body. Outside the central nervous system (CNS), ABCA1 functions in the biogenesis of high-density lipoprotein (HDL), where it mediates the efflux of cholesterol and phospholipids to apolipoprotein (apo) A-I. Deficiency of ABCA1 results in lack of circulating HDL and greatly reduced levels of apoA-I. ABCA1 is also expressed in cells within the CNS, but its roles in brain lipid metabolism are not yet fully understood. In the brain, glia synthesize the apolipoproteins involved in CNS lipid metabolism. Here we demonstrate that glial ABCA1 is required for cholesterol efflux to apoA-I and plays a key role in facilitating cholesterol efflux to apoE, which is the major apolipoprotein in the brain. In both astrocytes and microglia, ABCA1 deficiency reduces lipid efflux to exogenous apoE. The impaired ability to efflux lipids in ABCA1-/- glia results in lipid accumulation in both astrocytes and microglia under normal culture conditions. Additionally, apoE secretion is compromised in ABCA1-/- astrocytes and microglia. In vivo, deficiency of ABCA1 results in a 65% decrease in apoE levels in whole brain, and a 75-80% decrease in apoE levels in hippocampus and striatum. Additionally, the effect of ABCA1 on apoE is selective, as apoJ levels are unchanged in brains of ABCA1-/- mice. Taken together, these results show that glial ABCA1 is a key influence on apoE metabolism in the CNS.
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ABCA1 deficiency increases inflammatory response and lipid accumulation in microglia.
“Furthermore, ABCA1 deficiency has been shown to increase inflammatory response and lipid accumulation in microglia. 54 , 55”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [55]
ABCA1 levels regulate Aβ deposition in vivo.
“Moreover, animal studies have demonstrated that ABCA1 levels regulate A deposition in vivo (Hirsch-Reinshagen et al., 2004;Wahrle et al., 2004Wahrle et al., , 2005Wahrle et al., , 2008;;Koldamova et al., 2005).”
From microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain (2015) · cites this paper as Hirsch-Reinshagen et al., 2004
ABCA1 has a critical role in Aβ metabolism and accumulation.
“Several lines of data strongly support that ABCA1 has a critical role in Aβ metabolism and accumulation.”
From miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression (2012) · cites this paper as Hirsch-Reinshagen et al., 2004
Overexpression 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 Hirsch-Reinshagen et al., 2004
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 Hirsch-Reinshagen et al., 2004
In the brain, the level of ABCA1 modulates the extent of apoE lipidation and apoE levels.
“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 [29]
Brain levels of the cholesterol transporter ATP binding cassette A1 (ABCA1) alter the amount of apoE and the extent of apoE lipidation in mice.
“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 [29]
Both overexpression and deletion of ABCA1 in the mouse brain result in a decrease in apoE protein level.
“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 [29]
Lipids are loaded onto APOE via transmembrane ATP-binding cassette transporters such as ABCA1 and ABCG1.
“Lipids are loaded onto APOE via transmembrane ATP-binding cassette (ABC) transporters such as ABCA1 and ABCG1 (ref. 98) (Fig. 2a).”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [98]
apoE from ABCA1 knock-out mice is very poorly lipidated both in the periphery and in the brain, compared to wild type mice.
“As expected, apoE from ABCA1 knock-out mice was very poorly lipidated both in the periphery and in the brain, compared to wild type mice.”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Hirsch-Reinshagen et al., 2004
Genetic deletion of ABCA1 leads to a significant reduction in steady-state apoE protein levels in the brain and CSF as well as in the plasma.
“Genetic deletion of ABCA1 led to a significant reduction in steady-state apoE protein levels in the brain and CSF as well as in the plasma (Hirsch-Reinshagen et al., 2004; Wahrle et al., 2004), suggesting that poorly lipidated apoE is more rapidly catabolized.”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Hirsch-Reinshagen et al., 2004
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References 83 · Cited by 385
- Authors
- Hirsch-Reinshagen, V., Zhou, S., Burgess, B. L., Bernier, L., McIsaac, S. A., Chan, J. Y., Tansley, G. H., Cohn, J. S., Hayden, M. R., & Wellington, C. L.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- Wellington, Cheryl L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-09
- Volume
- 279
- Issue
- 39
- Pages
- 41197-41207
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2124927590
- Cited by
- 385
- References
- 83
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 17 · 2023: 18 · 2022: 21 · 2021: 17 · 2020: 19 · 2019: 16 · 2018: 8 · 2017: 16 · 2016: 17 · 2015: 18 · 2014: 21 · 2013: 14 · 2012: 20
- FWCI
- 19.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Heart and Stroke Foundation of British Columbia and Yukon
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- ABCA1, apolipoprotein E, apolipoprotein A-I, cholesterol efflux, brain lipid metabolism, astrocytes, microglia, glial cells, apoE secretion, hippocampus, striatum, lipid accumulation
- MeSH terms
- Animals, Apolipoproteins, Apolipoproteins E, Astrocytes, Biological Transport, Brain, Central Nervous System, Cerebellum, Cholesterol, Lipoproteins, HDL, Mice, Inbred C57BL, Mice, Inbred DBA, Microscopy, Fluorescence, Blotting, Western, Microglia, Mice, Knockout, ATP-Binding Cassette Transporters, Transgenes, Lipid Metabolism, Mice, ATP Binding Cassette Transporter 1
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