APOE4 impairs neuron‐astrocyte coupling of fatty acid metabolism

Abstract Background As the strongest genetic risk factor for late‐onset Alzheimer’s disease, the ε4 variant of apolipoprotein E (APOE4) is known to perturb both lipid homeostasis and energy metabolism in brain. However, the mechanistic role of APOE4 in modulating the bioenergetic aspects of lipid species, and its connection with cell‐type‐specific mitochondrial phenotypes are not well understood. Method Here, in individual‐ and co‐culture models of primary neurons and astrocytes from humanized APOE3 or APOE4 knockin mice, we describe a loss‐of‐function role of APOE4 in regulating key mechanisms controlling neuron‐astrocyte coupling of lipid metabolism, from neuronal storage of fatty acids (FAs) in lipid droplets (LDs), to the mobilization of neuronal LDs and transport of FAs to astrocytes, and eventually to the energetic degradation of FAs in astrocytes. Result Compared to APOE3, APOE4 decreases the sequestering of free fatty acids (FAs) in neuronal lipid droplets (LDs), elevates FA levels and leads to mitochondrial‐ and neuronal dysfunction. These neuronal LDs are eliminated upon astrocyte exposure and FAs are transported to astrocytes together with APOE, with APOE4 in either neurons or astrocytes diminishing the transport efficiency. In APOE4 astrocytes, increased mitochondrial fragmentation underlies a metabolic shift towards enhanced glucose metabolism and reduced FA β‐oxidation, which further elicits astrocytic LD accumulation. Moreover, the lesser capacity in eliminating neuronal lipids and performing β‐oxidation results in compromised ability of APOE4 astrocytes in providing metabolic‐ and synaptic support to neurons. Conclusion These data support the coupling of neuron lipid homeostasis, astrocytic FA degradation with cell‐specific mitochondrial function, which is essential to protect neurons from bioenergetic deficits and lipotoxicity. Further, our findings reveal the mechanistic basis of APOE4 in disrupting inter‐cellular FA metabolism in brain that may underlie the exaggerated lipid dyshomeostasis and bioenergetic decline, and increased AD risk for APOE4 carriers.