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ApoE4 disrupts interaction of sortilin with fatty acid-binding protein 7 essential to promote lipid signaling

Item Type:Preprint
Title:ApoE4 disrupts interaction of sortilin with fatty acid-binding protein 7 essential to promote lipid signaling
Creators Name:Asaro, A. and Sinha, R. and Bakun, M. and Kalnytska, O. and Carlo-Spiewok, A.S. and Rubel, T. and Rozeboom, A. and Dadlez, M. and Kaminska, B. and Aronica, E. and Malik, A.R. and Willnow, T.E.
Abstract:Sortilin is a receptor for neuronal uptake of apolipoprotein E. 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 apoE3 but is lost with apoE4, 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 (FABP) 7, 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 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.
Keywords:Alzheimer's Disease, Fatty Acid Binding Protein, Polyunsaturated Fatty Acids, Protein Sorting, VPS10P Domain Receptors, Animals, Mice
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2021.05.20.444938
Date:20 May 2021
Official Publication:https://doi.org/10.1101/2021.05.20.444938
Related to:
https://edoc.mdc-berlin.de/20942/Final version

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