Open AccessApoE4 disrupts interaction of sortilin with fatty acid-binding protein 7 essential to promote lipid signaling
Author(s) -
Antonino Asaro,
Rishabhdev Sinha,
Magda Bakun,
Oleksandra Kalnytska,
Anne-Sophie Carlo-Spiewok,
Tymon Rubel,
Annemieke Rozeboom,
Michał Dadlez,
Bożena Kamińska,
Eleonora Aronica,
Anna R. Malik,
Thomas E. Willnow
Publication year - 2021
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.258894
Subject(s) - biology , neuroprotection , apolipoprotein e , intracellular , lipid metabolism , fatty acid binding protein , microbiology and biotechnology , biochemistry , signal transduction , extracellular , lipid signaling , receptor , gene , neuroscience , medicine , disease
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.