The low-density lipoprotein (LDL) receptor-related protein (LRP) is a multifunctional receptor in the CNS that binds both apolipoprotein E (apoE) and activated alpha2-macroglobulin (alpha2M*); all 3 proteins are genetically associated with Alzheimer disease (AD). In this study we found an 85% increase in LRP levels in human AD brain frontal cortex, along with an increased level of the LRP ligands, apoE, and alpha2M. We speculated that LRP levels might be increased in response to the increased levels of its ligands, apoE, and alpha2M*. To test this hypothesis we examined the effects of alpha2M* on LRP in primary cultures. Treatment of neurons with alpha2M* significantly increased LRP levels (by 92%). This increase was prevented by coculture with receptor-associated protein (RAP), which blocks binding of LRP ligands to LRP Native alpha2M or RAP alone did not change LRP levels in vitro. We also found that alpha2M* stimulated activation of astrocytes in vitro and promoted the levels of LRP by 65%. These data indicate 1) the LRP ligand alpha2M* increases levels of LRP in primary neuronal and astrocytic cultures, 2) alpha2M*-induction of LRP levels in vitro depends on binding to LRP, and 3) LRP levels are increased in AD brain, perhaps in response to the increased levels of alpha2M.