LDL RECEPTOR-RELATED PROTEIN, A MULTIFUNCTIONAL APOE RECEPTOR, BINDS SECRETED BETA-AMYLOID PRECURSOR PROTEIN AND MEDIATES ITS DEGRADATION

The secreted form of beta-amyloid precursor protein (APP) containing t he Kunitz proteinase inhibitor (KPI) domain, also called protease nexi n II, is internalized and degraded by cells. We show that the low dens ity lipoprotein (LDL) receptor-related protein (LRP) is responsible fo r the endocytosis of secreted APP. APP(S)770 degradation is inhibited by an LRP antagonist called the receptor-associated protein (RAP) and by LRP antibodies and is greatly diminished in fibroblasts genetically deficient in LRP. APP(S)695, which lacks the KPI domain, isa poor LRP ligand, Since LRP also binds apolipoprotein E (apoE)-enriched lipopro teins and inheritance of the epsilon 4 allele of the apoE gene is a ri sk factor for Alzheimer's disease (AD), these data link in a single me tabolic pathway two molecules strongly implicated in the pathophysiolo gy of AD.