Isolation and characterization of a human cDNA demonstrated a novel lipoprotein receptor designated apolipoprotein E receptor 2 (apoER2). The new receptor consists of five functional domains resembling the low density lipoprotein (LDL) and very low density lipoprotein (VLDL) receptors. LDL receptor deficient Chinese hamster ovary cells expressing human apoER2 bound apoE rich -migrating VLDL with high affinity and internalized. LDL was bound with much lower affinity to these cells. The 4.5-and 8.5-kb mRNAs for the receptor were most highly expressed in human brain and placenta. In rabbit tissues, multiple species of the mRNA with 4, 4.5, 5.5, 8.5, and 11 kb were detected most intensely in brain and testis and, to a much lesser extent, in ovary, but were undetectable in other tissues. In rat adrenal pheochromocytoma PC12 cells, the receptor mRNA was induced by treatment of the cells with nerve growth factor. The receptor transcripts were detectable most intensely in the cerebellar cortex, choroid plexus, ependyma, hippocampus, olfactory bulb and, to a much lesser extent, in the cerebral cortex as revealed by in situ hybridization histochemistry. In the cerebellar cortex, the receptor transcripts were densely deposited in Purkinje cell somata.Receptor-mediated endocytosis of plasma lipoproteins plays an important role in the metabolism of cholesterol and triglyceride in the body. The low density lipoprotein (LDL) 1 receptor, one of the best characterized cell surface receptors, mediates cholesterol homeostasis in the body (1). The LDL receptor binds apolipoprotein B-100 containing LDL and apolipoprotein E (apoE)-containing lipoproteins, whereas the recently found very low density lipoprotein (VLDL) receptor binds only apoEcontaining lipoproteins (2, 3). Both the LDL receptor (4 -7) and VLDL receptor (2, 8 -14) consist of five functional domains: (i) an amino-terminal ligand binding domain composed of multiple cysteine-rich repeats; (ii) an epidermal growth factor (EGF) precursor homology domain, which mediates the acid-dependent dissociation of the ligands from the LDL receptor (15); (iii) an O-linked sugar domain; (iv) a transmembrane domain; and (v) a cytoplasmic domain with a coated pit targeting signal (16). Genetic deficiencies of the LDL receptor give rise to familial hypercholesterolemia, one of the most common genetic diseases in humans (17). Mutations in the chicken VLDL receptor gene lead to the failure to produce offspring (13, 18).Lipoprotein metabolism in the central nervous system (CNS) has been poorly understood, despite the importance of lipids in some specialized neural membranes, such as myelin. Most of lipids in the CNS are actively synthesized in the CNS itself and deposited in large amounts during the early phase of development (19, 20). The rate of cholesterol and fatty acid synthesis in the brain is high during the myelinating period and declines thereafter (19,20). Although most of lipids in the brain are believed to be synthesized within the brain itself, small amounts of cholesterol (21)...