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

Sortilin (SORT1) is a lipoprotein receptor that shows genome-wide association with hypercholesterolaemia, explained by its ability to control hepatic output of lipoproteins. Although SORT1 also shows genome-wide association with Alzheimer disease and frontotemporal lobe dementia, the most prevalent forms of age-related dementias, sortilin’s contribution to human brain lipid metabolism and health remains unclear. Here we show that sortilin mediates neuronal uptake of polyunsaturated fatty acids carried by apolipoprotein E (apoE). Using humanized mouse strains and induced pluripotent stem cell-based cell models of brain lipid homeostasis, we demonstrate that internalized lipids are converted into ligands for peroxisome proliferator-activated receptor alpha inducing transcription profiles that enable neurons to use long-chain fatty acids as metabolic fuel when glucose is limited. This pathway works with apoE3 but cannot operate with the Alzheimer disease risk factor apoE4, which disrupts sortilin’s endocytic activity. Our data indicate a role for the lipoprotein receptor sortilin in metabolic fuel choice in neurons, which may be crucial when glucose supply is limited, such as in the ageing brain.