Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel

SUMMARY Sortilin ( SORT1 ) is a lipoprotein receptor that shows genome-wide association with hypercholesterolemia, explained by its ability to control hepatic output of lipoproteins. Remarkably, SORT1 also shows genome-wide association with Alzheimer disease (AD) and frontotemporal lobe dementia, the most prevalent forms of age-related dementias. Yet, sortilin’s contribution to human brain lipid metabolism and health remains unclear. Using humanized mouse strains and iPSC-based cell models of brain lipid homeostasis, we document that sortilin mediates neuronal uptake of polyunsaturated fatty acids carried by apoE. Internalized lipids are converted into ligands for PPARα, inducing transcription profiles that enable neurons to use long-chain fatty acids as metabolic fuel. This pathway works with apoE3, but is lost with the AD risk factor apoE4, which disrupts sortilin’s endocytic activity. We document a role for the lipoprotein receptor sortilin in metabolic fuel choice in neurons, possibly crucial when supply with glucose is limited, as in the aging brain.