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Featured ArticleResearch Articles, Neurobiology of Disease

ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes

Varun Rawat, Shaowei Wang, Jian Sima, Roni Bar, Ori Liraz, Usha Gundimeda, Trusha Parekh, Jamie Chan, Jan O. Johansson, Chongren Tang, Helena C. Chui, Michael G. Harrington, Daniel M. Michaelson and Hussein N. Yassine
Journal of Neuroscience 27 November 2019, 39 (48) 9611-9622; DOI: https://doi.org/10.1523/JNEUROSCI.1400-19.2019
Varun Rawat
1University of Southern California, Los Angeles, California, 90033,
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Shaowei Wang
1University of Southern California, Los Angeles, California, 90033,
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Jian Sima
1University of Southern California, Los Angeles, California, 90033,
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Roni Bar
2Tel Aviv University, Tel Aviv 6997801, Israel,
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Ori Liraz
2Tel Aviv University, Tel Aviv 6997801, Israel,
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Usha Gundimeda
1University of Southern California, Los Angeles, California, 90033,
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Trusha Parekh
1University of Southern California, Los Angeles, California, 90033,
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Jamie Chan
1University of Southern California, Los Angeles, California, 90033,
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Jan O. Johansson
3Artery Therapeutics, Inc., San Ramon, California 94583,
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Chongren Tang
4University of Washington, Seattle, Washington 98195, and
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Helena C. Chui
1University of Southern California, Los Angeles, California, 90033,
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Michael G. Harrington
5Huntington Medical Research Institute, Pasadena, California 91105
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Daniel M. Michaelson
2Tel Aviv University, Tel Aviv 6997801, Israel,
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Hussein N. Yassine
1University of Southern California, Los Angeles, California, 90033,
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Abstract

The APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE protein aggregation plays a central role in AD pathology, including the accumulation of β-amyloid (Aβ). Lipid-poor ApoE4 protein is prone to aggregate and lipidating ApoE4 protects it from aggregation. The mechanisms regulating ApoE4 aggregation in vivo are surprisingly not known. ApoE lipidation is controlled by the activity of the ATP binding cassette A1 (ABCA1). ABCA1 recycling and degradation is regulated by ADP-ribosylation factor 6 (ARF6). We found that ApoE4 promoted greater expression of ARF6 compared with ApoE3, trapping ABCA1 in late-endosomes and impairing its recycling to the cell membrane. This was associated with lower ABCA1-mediated cholesterol efflux activity, a greater percentage of lipid-free ApoE particles, and lower Aβ degradation capacity. Human CSF from APOE ε4/ε4 carriers showed a lower ability to induce ABCA1-mediated cholesterol efflux activity and greater percentage of aggregated ApoE protein compared with CSF from APOE ε3/ε3 carriers. Enhancing ABCA1 activity rescued impaired Aβ degradation in ApoE4-treated cells and reduced both ApoE and ABCA1 aggregation in the hippocampus of male ApoE4-targeted replacement mice. Together, our data demonstrate that aggregated and lipid-poor ApoE4 increases ABCA1 aggregation and decreases ABCA1 cell membrane recycling. Enhancing ABCA1 activity to reduce ApoE and ABCA1 aggregation is a potential therapeutic strategy for the prevention of ApoE4 aggregation-driven pathology.

SIGNIFICANCE STATEMENT ApoE protein plays a key role in the formation of amyloid plaques, a hallmark of Alzheimer's disease (AD). ApoE4 is more aggregated and hypolipidated compared with ApoE3, but whether enhancing ApoE lipidation in vivo can reverse ApoE aggregation is not known. ApoE lipidation is controlled by the activity of the ATP binding cassette A1 (ABCA1). In this study, we demonstrated that the greater propensity of lipid-poor ApoE4 to aggregate decreased ABCA1 membrane recycling and its ability to lipidate ApoE. Importantly, enhancing ABCA1 activity to lipidate ApoE reduced ApoE and ABCA1 aggregation. This work provides critical insights into the interactions among ABCA1, ApoE lipidation and aggregation, and underscores the promise of stabilizing ABCA1 activity to prevent ApoE-driven aggregation pathology.

  • ABCA1
  • aggregation
  • Alzheimer's disease
  • ApoE
  • lipids
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The Journal of Neuroscience: 39 (48)
Journal of Neuroscience
Vol. 39, Issue 48
27 Nov 2019
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ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes
Varun Rawat, Shaowei Wang, Jian Sima, Roni Bar, Ori Liraz, Usha Gundimeda, Trusha Parekh, Jamie Chan, Jan O. Johansson, Chongren Tang, Helena C. Chui, Michael G. Harrington, Daniel M. Michaelson, Hussein N. Yassine
Journal of Neuroscience 27 November 2019, 39 (48) 9611-9622; DOI: 10.1523/JNEUROSCI.1400-19.2019

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ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes
Varun Rawat, Shaowei Wang, Jian Sima, Roni Bar, Ori Liraz, Usha Gundimeda, Trusha Parekh, Jamie Chan, Jan O. Johansson, Chongren Tang, Helena C. Chui, Michael G. Harrington, Daniel M. Michaelson, Hussein N. Yassine
Journal of Neuroscience 27 November 2019, 39 (48) 9611-9622; DOI: 10.1523/JNEUROSCI.1400-19.2019
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Keywords

  • ABCA1
  • aggregation
  • Alzheimer's disease
  • ApoE
  • lipids

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