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ApoE4 disrupts interaction of sortilin with fatty acid-binding protein 7 essential to promote lipid signaling
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Abstract
Sortilin is a neuronal receptor for apolipoprotein E (apoE). Sortilin-dependent uptake of lipidated apoE promotes conversion of polyunsaturated fatty acids (PUFA) into neuromodulators that induce anti-inflammatory gene expression in the brain. This neuroprotective pathway works with the apoE3 variant but is lost with the apoE4 variant, the main risk factor for Alzheimer's disease (AD). Here, we elucidated steps in cellular handling of lipids through sortilin, and why they are disrupted by apoE4. Combining unbiased proteome screens with analyses in mouse models, we uncover interaction of sortilin with fatty acid-binding protein 7 (FABP7), the intracellular carrier for PUFA in the brain. In the presence of apoE3, sortilin promotes functional expression of FABP7 and its ability to elicit lipid-dependent gene transcription. By contrast, apoE4 binding blocks sortilin-mediated sorting, causing catabolism of FABP7 and impairing lipid signaling. Reduced FABP7 levels in the brain of AD patients expressing apoE4 substantiate the relevance of these interactions for neuronal lipid homeostasis. Taken together, we document interaction of sortilin with mediators of extracellular and intracellular lipid transport that provides a mechanistic explanation for loss of a neuroprotective lipid metabolism in AD.
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In mouse models, sortilin-dependent uptake of lipids works well with apoE3, the most common isoform of the lipid carrier in humans.
“In mouse models, sortilin-dependent uptake of lipids works well with apoE3, the most common isoform of the lipid carrier in humans.”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [15]
Sortilin-dependent lipid uptake is disrupted by lipidated apoE4, which blocks sortilin recycling and ceases receptor-mediated ligand uptake into cells.
“However, this function of sortilin is disrupted when binding lipidated apoE4, as this apoE variant blocks sortilin recycling and ceases receptor-mediated ligand uptake into cells14,15.”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [15]
ApoE3 uptake requires the interaction of sortilin with the carrier FABP7, facilitating intraneuronal lipid transport.
“As shown in established cell lines before, apoE3 uptake also requires the interaction of sortilin with the carrier FABP7, facilitating intraneuronal lipid transport15.”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [15]
Sortilin interacts with FABP7.
“As well as by quantity, sortilin may also distinguish itself from other apoE receptors by functionality as it interacts with FABP7 (ref. 15).”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [15]
Sortilin is essential for proper sorting and stable expression of FABP7 in established cell lines.
“Sortilin is essential for proper sorting and stable expression of FABP7 in established cell lines15, a mechanism now supported by data in human neurons (Fig. 6h).”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [15]
Binding of apoE4 traps internalized sortilin in early endosomes, preventing discharge of cargo and recycling to the cell surface.
“Similarly to other receptors bound by apoE73,74, binding of apoE4 traps internalized sortilin in early endosome, preventing discharge of cargo and recycling to the cell surface15.”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [15]
FABP7 is a known sortilin interactor and an intracellular carrier for PUFAs and eCBs.
“Loss of sortilin coincided with reduced levels of FABP7, a known sortilin interactor15 and intracellular carrier for PUFAs and eCBs (Fig. 6h)”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [15]
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Citations
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Sorted by citations
Greda, A. K., Gomes, J. P., Schmidt-Krueger, V., Zurawska-Plaksej, E., Fritsche-Guenther, R., Rudolph, I.-M., Telugu, N. S., Cömert, C., Kirwan, J., Kunz, S., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01389-5 · Cited by 21
Self-citation
Metadata
- Authors
- Asaro, A., Sinha, R., Bakun, M., Kalnytska, O., Carlo-Spiewok, A.-S., Rubel, T., Rozeboom, A., Dadlez, M., Kaminska, B., Aronica, E., Malik, A. R., & Willnow, T. E.
- Affiliations
- Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany
- Mass Spectrometry Laboratory, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland
- Warsaw University of Technology, Institute of Radioelectronics and Multimedia Technology, 00-665 Warsaw, Poland
- Department of (Neuro) Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, 1105AZ Amsterdam, The Netherlands
- Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2021-10-15
- Volume
- 134
- Issue
- 20
- ISSN
- 0021-9533
- 1477-9137
- PMC
- PMC8572006
- Cited by
- 31
- References
- 8
- Language
- en
- Funders
- European Research Council (BeyOND No. 335692)
- Helmholtz Association
- Alzheimer Forschung Initiative (18003)
- Novo Nordisk Foundation (NNF18OC0033928)
- Fundacja na rzecz Nauki Polskiej (POIR.04.04.00 00 5CEF/18 00)
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