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Apolipoprotein E4 disrupts the neuroprotective action of sortilin in neuronal lipid metabolism and endocannabinoid signaling
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Abstract
Introduction: Apolipoprotein E (apoE) is a carrier for brain lipids and the most important genetic risk factor for Alzheimer's disease (AD). ApoE binds the receptor sortilin, which mediates uptake of apoE‐bound cargo into neurons. The significance of this uptake route for brain lipid homeostasis and AD risk seen with apoE4, but not apoE3, remains unresolved. Methods: Combining neurolipidomics in patient specimens with functional studies in mouse models, we interrogated apoE isoform–specific functions for sortilin in brain lipid metabolism and AD. Results: Sortilin directs the uptake and conversion of polyunsaturated fatty acids into endocannabinoids, lipid‐based neurotransmitters that act through nuclear receptors to sustain neuroprotective gene expression in the brain. This sortilin function requires apoE3, but is disrupted by binding of apoE4, compromising neuronal endocannabinoid metabolism and action. Discussion: We uncovered the significance of neuronal apoE receptor sortilin in facilitating neuroprotective actions of brain lipids, and its relevance for AD risk seen with apoE4.
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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 [14]
Levels of PUFAs and endocannabinoids are decreased in the brains of E3KO, E4WT, and E4KO mice compared to E3WT animals.
“We previously reported that levels of PUFAs and endocannabinoids (eCBs) were decreased in the brains of E3KO, E4WT and E4KO mice as compared to E3WT animals14.”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [14]
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 [14]
Loss of PUFAs is attributed to a prominent role of sortilin in neuronal uptake of lipidated apoE, providing essential lipids for cellular lipid metabolism and action.
“Loss of PUFAs is attributed to a prominent role of the receptor in neuronal uptake of lipidated apoE, providing essential lipids for cellular lipid metabolism and action10,14.”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [14]
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Citations
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Self-citation
Metadata
- Authors
- Asaro, A., Carlo‐Spiewok, A., Malik, A. R., Rothe, M., Schipke, C. G., Peters, O., Heeren, J., & Willnow, T. E.
- Affiliations
- Max‐Delbrueck‐Center for Molecular Medicine Berlin Germany
- Lipidomix GmbH Berlin Germany
- Experimental and Clinical Research Center Charité ‐ Universitätsmedizin Berlin and Berlin Institute of Health Berlin Germany
- Department of Psychiatry Charité ‐ Universitätsmedizin Berlin Berlin Germany
- Biochemistry and Molecular Cell Biology University Medical Center Hamburg‐Eppendorf Hamburg Germany
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2020-06-25
- Volume
- 16
- Issue
- 9
- Pages
- 1248-1258
- ISSN
- 1552-5260
- 1552-5279
- Cited by
- 38
- References
- 9
- Language
- en
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