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

Antonino Asaro,Anna R Malik,Bozena Kaminska,Eleonora Aronica,Magda Bakun,Anne-Sophie Carlo-Spiewok,Tymon Rubel,Thomas E Willnow,Michal Dadlez,Annemieke Rozeboom,Rishabhdev Sinha,Oleksandra Kalnytska

doi:10.1242/jcs.258894

Abstract

ABSTRACTSortilin 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.

Highlights

Apolipoprotein E is the main carrier for lipids in the brain
ApoE4 disrupts the ability of sortilin to promote stability and proper intracellular sorting of FABP7, essential for lipid signaling via PPARs. These findings identified a central role for sortilin in neuroprotective lipid metabolism by integrating extracellular and intracellular (FABP7) lipid transport processes; processes disrupted by apoE4-induced missorting of this receptor
To identify sortilin-dependent trafficking processes relevant for neuronal lipid metabolism and action, we applied an unbiased proteomics approach to identify novel receptor targets in neurons. This approach was based on our assumption that the loss of sortilin activity will result in aberrant distribution of so far unknown receptor ligands between cell surface and intracellular compartments

Summary

Introduction

Apolipoprotein E is the main carrier for lipids in the brain. It is released by astrocytes and microglia and delivers essential lipids to neurons that take up apoE-bound cargo through apoE receptors expressed on the neuronal cell surface (reviewed in (Holtzman et al, 2012)). Sortilin directs neuronal uptake and conversion of apoE-bound 3-polyunsaturated fatty acids (PUFA) into endocannabinoids (eCBs), neuromodulatory lipids that act via nuclear receptors of the PPAR family to induce an anti-inflammatory gene expression profile in the brain (Asaro et al, 2020). This neuroprotective action of sortilin is seen with apoE3 but lost when binding apoE4, disrupting neuronal eCB production and resulting in a pro-inflammatory state that may predispose the apoE4 brain to neurodegeneration (Asaro et al, 2020). The molecular mechanism of sortilin’s action in neuronal lipid homeostasis and why this activity is lost in the presence of apoE4 remains poorly understood

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