Apolipoprotein E-mediated lipid metabolism in the central nervous system plays an important role in cholesterol and phospholipid homeostasis of this organ, which is separated from the circulation by the blood-brain barrier. Moreover, in late-onset familial Alzheimer disease the frequency of the apolipoprotein E4 allele is significantly increased and the apoprotein is localized to extracellular plaques, one of the histological hallmarks of this disease. Recently, two distinct novel members of the low-density lipoprotein (LDL) receptor family, with the potential to bind apolipoprotein E and preferentially expressed in brain, have been characterized from human (D. Kim et al., 1996, J. Biol. Chem 271: 8373-8380) and chicken and mouse (S. Novak, et al., 1996, J. Biol. Chem. 271: 11732-11736). The human receptor, termed 'apolipoprotein E receptor 2,' is a seven ligand-binding repeat receptor harboring a unique insertion in the cytoplasmic domain of the protein. The novel receptor characterized in chicken and mouse was found to have eight binding repeats without such a cytoplasmic insertion. Despite the overall identity of more than 73%, based upon their structural differences (seven versus eight ligand-binding repeats) these receptors have been considered independent entities. However, here we demonstrate that both receptors in fact are encoded by corresponding genes and that differential splicing gives rise to structurally and possibly functionally distinct variants of this brain-specific member of the LDL receptor family.
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