Cleavage of ApoE R2 by γ-secretase, metalloproteases, and furin-like enzymes results in the liberation of the cytoplasmic, extracellular, and ligand binding domains. The cytoplasmic NPxY motif binds to PTB domain-containing adaptor proteins. Among these, FE65 and PSD95 couple ApoE R2 with APP or the NMDA receptor, respectively. ApoE R2 and NMDA receptor ligands modulate adaptor interactions, NMDA-mediated ion currents, and the proteolytic processing of both ApoE R2 and APP. ApoE R2 and the NMDA receptor also associate extracellularly. ApoE R2 binds ApoE-containing lipoproteins and the large modular protein, reelin. Reelin signaling through ApoE R2 is critical for neuronal migration and positioning in the developing brain. In the adult brain, ApoE R2 functions in hippocampal synapse maturation, synaptic plasticity, and memory formation.ApoE R2 is also expressed at the neuromuscular junction but does not appear to participate in the development or function of that structure. Deficits in ApoE R2, reelin, and ApoE function have been linked to several cognitive and mood disorders.