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

Abstract

Sortilin is a neuronal receptor for 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.

Exploring the Role of Lipid-Binding Proteins and Oxidative Stress in Neurodegenerative Disorders: A Focus on the Neuroprotective Effects of Nutraceutical Supplementation and Physical Exercise

“…Moreover, in AD brains of patients expressing ApoE ε4, there are reduced levels of FABP7, and this alters PUFA cerebral content and their role as anti-inflammatory molecules [ 105 ].…”

Deciphering Mechanisms of Action of Sortilin/Neurotensin Receptor-3 in the Proliferation Regulation of Colorectal and Other Cancers

“…Additionally, Sortilin/NTSR3 has been shown to interact with the receptor of Nerve Growth Factor (NGF), the p75 neurotrophin receptor (p75NTR), to trigger neuronal apoptosis induced by the precursor of Nerve Growth Factor (pro-NGF) [ 27 , 28 ] and the precursor of Brain-Derived Neurotrophic Factor (pro-BDNF) [ 29 , 30 ]. Recently, it was identified that Sortilin/NTSR3 acts as a receptor for the brain lipids carrier Apolipoprotein E (apoE), which confers the most important genetic risk factor for Alzheimer’s disease (AD), demonstrating the involvement of Sortilin/NTSR3 in the neuroprotective action of apoE in AD pathology [ 31 ]. Finally, the role of Sortilin/NTSR3 as a biomarker of risk in cardiovascular disorders in humans has been largely confirmed [ 32 , 33 ].…”

A Dichotomous Role for FABP7 in Sleep and Alzheimer’s Disease Pathogenesis: A Hypothesis

“…Moreover, recent evidence suggests that APOE and FABP7 may interact, with the APOE isoform determining the functional expression of FABP7 ( Asaro et al, 2021 ). In mouse brains expressing the ApoE ε3 isoform (the most common isoform), this transporter delivers lipids to the neuronal receptor sortilin, which mediates the transfer of lipids from the exterior of the cell to the interior ( Carlo et al, 2013 ).…”

“…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 ( Asaro et al, 2020 ). In a mouse model, sortilin was also shown to promote the stability of FABP7 in an APOE isoform-dependent manner, with ApoE ε3 promoting the proper intracellular sorting of FABP7 and ApoE ε4 disrupting it ( Asaro et al, 2021 ). APOE isoform-related differences in FABP7 have also been seen in humans ( Asaro et al, 2021 ).…”

“…In a mouse model, sortilin was also shown to promote the stability of FABP7 in an APOE isoform-dependent manner, with ApoE ε3 promoting the proper intracellular sorting of FABP7 and ApoE ε4 disrupting it ( Asaro et al, 2021 ). APOE isoform-related differences in FABP7 have also been seen in humans ( Asaro et al, 2021 ). Indeed, APOE ε 3/APOE ε 3 patients were observed to have significantly higher levels of FABP7 than APOE ε 4/APOE ε 4 patients, providing a novel connection between ApoE ε4 and FABP7 and suggesting that inhibition of FABP7 signaling may be one mechanism of ApoE ε4-induced AD development and/or progression.…”