ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes
| Autor: | Shaowei Wang, Ori Liraz, Jan O. Johansson, Helena C. Chui, Trusha Parekh, Chongren Tang, Roni Bar, Daniel M. Michaelson, Hussein N. Yassine, Jian Sima, Jamie Chan, Usha Gundimeda, Varun Rawat, Michael G. Harrington |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Apolipoprotein E Apolipoprotein E4 Mice Transgenic ATP-binding cassette transporter Lipid-anchored protein Protein aggregation Cell membrane Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Cricetinae polycyclic compounds medicine Animals Humans Cells Cultured Research Articles Aged Cell Line Transformed Aged 80 and over biology Chemistry Cholesterol General Neuroscience Cell Membrane Middle Aged Cell biology Mice Inbred C57BL Protein Transport 030104 developmental biology medicine.anatomical_structure ADP-Ribosylation Factor 6 Astrocytes ABCA1 biology.protein Female lipids (amino acids peptides and proteins) 030217 neurology & neurosurgery ATP Binding Cassette Transporter 1 HeLa Cells Protein Binding |
| Zdroj: | J Neurosci |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.1400-19.2019 |
| Popis: | TheAPOEε4 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 aggregationin vivoare 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 fromAPOEε4/ε4 carriers showed a lower ability to induce ABCA1-mediated cholesterol efflux activity and greater percentage of aggregated ApoE protein compared with CSF fromAPOEε3/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 STATEMENTApoE 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 lipidationin vivocan 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. |
| Databáze: | OpenAIRE |
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