TY - JOUR
T1 - ApoE4 disrupts interaction of sortilin with fatty acid-binding protein 7 essential to promote lipid signaling
AU - Asaro, Antonino
AU - Sinha, Rishabhdev
AU - Bakun, Magda
AU - Kalnytska, Oleksandra
AU - Carlo-Spiewok, Anne-Sophie
AU - Rubel, Tymon
AU - Rozeboom, Annemieke
AU - Dadlez, Michal
AU - Kaminska, Bozena
AU - Aronica, Eleonora
AU - Malik, Anna R.
AU - Willnow, Thomas E.
N1 - Funding Information: Studies were funded in part by the European Research Council (ERC) (BeyOND No. 335692), the Helmholtz Association (AMPro), the Alzheimer Forschung Initiative (#18003), and the Novo Nordisk Foundation (NNF18OC0033928) to T.E.W.; and by the Foundation for Polish Science (Fundacja na rzecz Nauki Polskiej) co–financed by the European Union under the European Regional Development Fund (Homing program, POIR.04.04.00 00 5CEF/18 00) to A.R.M. Equipment for surface proteomics was provided in part by the Centre for Preclinical Research and Technology (CePT), co-sponsored by the European Regional Development Fund and Innovative Economy, The National Cohesion Strategy of Poland. Deposited in PMC for immediate release. Publisher Copyright: © 2021. Published by The Company of Biologists Ltd
PY - 2021/10/1
Y1 - 2021/10/1
N2 - 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.
AB - 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.
KW - Alzheimer’s disease
KW - Fatty acid binding protein
KW - Polyunsaturated fatty acid
KW - Protein sorting
KW - VPS10P domain receptor
UR - http://www.scopus.com/inward/record.url?scp=85118856852&partnerID=8YFLogxK
U2 - https://doi.org/10.1242/jcs.258894
DO - https://doi.org/10.1242/jcs.258894
M3 - Article
C2 - 34557909
SN - 0021-9533
VL - 134
JO - Journal of Cell Science
JF - Journal of Cell Science
IS - 20
M1 - jcs258894
ER -