AVIAN AND MURINE LR8B AND HUMAN APOLIPOPROTEIN-E RECEPTOR-2 - DIFFERENTIALLY SPLICED PRODUCTS FROM CORRESPONDING GENES

Apolipoprotein E-mediated lipid metabolism in the central nervous syst em plays an important role in cholesterol and phospholipid homeostasis of this organ, which is separated from the circulation by the blood-b rain barrier. Moreover, in late-onset familial Alzheimer disease the f requency of the apolipoprotein E4 allele is significantly increased an d the apoprotein is localized to extracellular plaques, one of the his tological hallmarks of this disease. Recently, two distinct novel memb ers of the low-density lipoprotein (LDL) receptor family, with the pot ential to bind apolipoprotein E and preferentially expressed in brain, have been characterized from human (D. Kim et al., 1996, J. Biol. Che m. 271: 8373-8380) and chicken and mouse (S. Novak, et al., 1996, J. B iol. Chem. 271: 11732-11736). The human receptor, termed ''apolipoprot ein E receptor 2,'' is a seven ligand-binding repeat receptor harborin g a unique insertion in the cytoplasmic domain of the protein. The nov el receptor characterized in chicken and mouse was found to have eight binding repeats without such a cytoplasmic insertion. Despite the ove rall identity of more than 73%, based upon their structural difference s (seven versus eight ligand-binding repeats) these receptors have bee n considered independent entities. However, here we demonstrate that b oth receptors in fact are encoded by corresponding genes and that diff erential splicing gives rise to structurally and possibly functionally distinct variants of this brain-specific member of the LDL receptor f amily. (C) 1997 Academic Press.