Fig. 2.

Roles of distinct APOE isoforms in astrocyte-neuron communication. The liver X receptor (LXR) and retinoid X receptor (RXR) activation regulate APOE isoforms expression in astrocytes. ATP-binding cassette transporter (ABCA1) is responsible for apoE lipidation and secretion to the extracellular space, so as to lipidate apoE already present in the extracellular space. ApoE can be later on recognized by several neuronal lipid receptors including VLDL-receptor (VLDLR), LDLR, Low-density lipoprotein receptor-related protein 1 (LRP1), and heparan sulfate proteoglycans (HSPGs). The distinct apoE isoform lipidation status promotes distinct receptor affinities. The apoE4 isoform presents alterations in its physiological pathways compared to other isoforms, such as low lipidation status, the formation of non-lipidated apoE4 aggregates, and a poor lipid turnover towards astrocytes, which leads to neuronal lipid-droplet accumulation. This promotes mitochondrial damage and reactive oxygen species (ROS) production. Moreover, apoE4 promotes endosome formation and degradation of synaptic receptors like AMPA or NMDA, leading to impaired synaptic function