The low-density lipoprotein receptor-related protein, a multifunctional apolipoprotein E receptor, modulates hippocampal neurite development

The ε4 allele of apolipoprotein E (apoE) is an important risk factor for Alzheimer's disease. A major neuronal receptor for apoE within the brain is the low-density lipoprotein receptor-related protein (LRP). Using primary cultured hippocampal neurons, we examined the role of LRP in early neuronal development. LRP, as well as a 39-kDa protein that regulates its activity, is localized abundantly in developing neurons. Both the 39-kDa protein and an anti-LRP antibody inhibited neurite outgrowth of primary hippocampal neurons cultured in either serum-containing medium or on cortical astrocyte monolayers in serum-free medium. It is noteworthy that microtubule-associated protein-2 immunoreactive process outgrowth was decreased significantly in hippocampal neurons cultured on cortical astrocytes derived from apoE- deficient mice and was not diminished further following incubation with LRP inhibitors. Thus, these results suggest that LRP can influence aspects of neuronal process development and that apoE-containing lipoproteins may be one of the major LRP ligands that can contribute to this process.