Apolipoprotein E (ApoE), a major component of LDL and VLDL lipoproteins circulating in blood, mediates uptake of lipoproteins into cells by binding to ApoE receptors, principally the LDL-receptor (Goldstein and Brown, 2015). ApoE is also highly expressed in brain, primarily in astrocytes, but its function in brain remains unclear (Holtzman et al., 2012; Wang and Eckel, 2014). In addition to LDL-receptors, several related ApoE-receptors are expressed throughout the body. Many of these other ApoE-receptors bind additional ligands and perform central functions during development. For example, the LDL-receptor-related proteins VLDLR and ApoER2 bind reelin and regulate cortical development (Trommsdorff et al., 1999), LDL-receptor-related proteins 5 and 6 (Lrp5 and Lrp6) are co-receptors for wnts (Tamai et al., 2000), and LDL-receptor-related protein Lrp2 is an auxiliary receptor for sonic hedgehog (Christ et al., 2012). Moreover, ApoE exhibits signaling properties in dissociated cultures of rodent neurons, and activates MAP-kinases (Ohkubo et al., 2001; Qiu et al., 2004). Several MAP-kinases are prominently expressed in brain, including the MAP-kinase kinase kinase DLK (for ‘dual leucine-zipper kinase’), which has been implicated both in the degeneration and
