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

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 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.

Finding memo: versatile interactions of the VPS10p-Domain receptors in Alzheimer’s disease

“…These observations were in marked contrast to SorLA deficient mice that exhibited no accumulation of ApoE, supporting the model of Sortilin's direct effect on ApoE and Aβ turnover [93]. Most recently, the same research group studied the relevance of the Sortilin-mediated uptake of ApoE for brain lipid metabolism [243,244]. They found that Sortilin is required to accumulate and facilitate the metabolism of polyunsaturated fatty acid into endocannabinoids; lipids with potent anti-inflammatory and neuroprotective functions.…”

“…The combined findings are schematized in (Fig. 5, BOX D) and suggest a protective role of Sortilin in AD by lowering Aβ levels, reducing production of neuroinflammatory cytokines [244,245], stimulating synapse function, and sustaining neuron viability.…”

Finding Memo: Versatile interactions of the VPS10p receptors in Alzheimer’s disease

“…The authors explain this apparent paradox by ApoE4 being unable to uncouple from sortilin in the endosomal compartment, which disrupts recycling and re-exposure of the receptor at the plasma membrane. The combined findings suggest a protective role of sortilin in AD by lowering A levels, reducing production of neuroinflammatory cytokines [182,183], stimulating synapse function, and sustaining neuron viability (Figure 5…”

“…However, the absence of sortilin significantly attenuated the uptake of ApoE-A complexes, demonstrating that impaired ApoE clearence by sortilin causes accumulation of Aβ in the brain [92]. Most recently, the same research group went on to study the relevance of the sortilin-mediated uptake of ApoE for brain lipid metabolism [181,182]. They found that sortilin is required to accumulate and facilitate the metabolism of polyunsaturated fatty acid into endocannabinoids; lipids with potent anti-inflammatory and neuroprotective functions.…”