The ApoE receptors Vldlr and Apoer2 in central nervous system function and disease

Abstract

The LDL receptor (LDLR) family has long been studied for its role in cholesterol transport and metabolism; however, the identification of ApoE4, an LDLR ligand, as a genetic risk factor for late-onset Alzheimer's disease has focused attention on the role this receptor family plays in the CNS. Surprisingly, it was discovered that two LDLR family members, ApoE receptor 2 (Apoer2) and VLDL receptor (Vldlr), play key roles in brain development and adult synaptic plasticity, primarily by mediating Reelin signaling. This review focuses on Apoer2 and Vldlr signaling in the CNS and its role in human disease.

Keywords: Alzheimer’s disease; apolipoprotein E; apolipoprotein E receptor 2; apolipoproteins; cell signaling; endocytosis; lipoprotein receptors; neurons; very low density lipoprotein receptor.

Fig. 1.

Structure of Reelin and the ApoE receptors, Ldlr, Vldlr, and Apoer2. Reelin comprises a signal peptide, an F-spondin-like domain, eight RRs that each contain a “A” and “B” parts separated by an EGF motif, and a C-terminal domain. Reelin is cleaved at two sites between RR2/RR3 and RR6/RR7. The ApoE receptors contain an extracellular ligand binding domain, EGF-precursor homology domain, an alternatively spliced OLS domain, a single transmembrane domain, and a short ICD containing one to three NPXY motifs. Apoer2 has an alternatively spliced 59 amino acid ICD.

Fig. 2.

Reelin signaling cascade. The central fragment of Reelin binds to Vldlr and Apoer2, which clusters the two receptors and activates Dab1 signaling. Dab1 activates SFKs, which phosphorylate NMDARs, enhancing LTP and preventing NMDA endocytosis. NMDAR activation requires the presence of the alternatively spliced exon 19, which interacts with scaffolding protein PSD-95. Aβ has opposing effects on NMDAR phosphorylation and promotes NMDAR endocytosis, primarily through striatal-enriched protein tyrosine phosphatase (STEP) activation. Dab1 also activates PI3K, which leads to inhibition of GSK3β reduction of tau phosphorylation. PI3K additionally activates Cdc42, which leads to inhibitory phosphorylation of cofilin and promotes actin polymerization and dendritic spine growth. The N-t fragment of Reelin binds to EphB receptors and can induce EphB signaling (28). [Modified from (87).]