The distribution pattern of apolipoprotein E (apoE) in cortical neurons in culture resembles that of low-density lipoprotein receptor-related protein 4 (LRP4). Both proteins are distributed in a punctate manner on the cell surface throughout neurons, including somas and dendrites. This finding prompted us to examine whether apoE is a ligand for LRP4 in the rat brain. ApoE and LRP4 from both Cos7 cells heterologous expressing LRP4 and brain homogenate were co-immunoprecipitated. We then examined the effect of antibody against the ligand-binding domain of LRP4 (anti-LB). Anti-LB applied to neuronal cells in culture down-regulated MAP2-immunoreactive neurons, reduced the viability of neurons and impaired synaptic structure. This effect was possibly due to a blockade of the binding of extraneuronal ligands, such as apoE/cholesterol, to LRP4 protein, since anti-LB suppressed binding of apoE to the LRP4 heterologously expressed in Cos7 cells. These results suggest that apoE is an endogenous ligand for LRP4 and may play a role as a receptor for extracellular signals, including those from glial cells, in the maintenance of the viability of neurons.