Role of apolipoprotein E receptors in regulating the differential in vivo neurotrophic effects of apolipoprotein E

Apolipoprotein E (apoE) is known to bind to at least five receptors, includ ing the low-density lipoprotein (LDL) receptor-related protein (LRP), very low density LDL receptor (VLDL-R), LDL-R, apoE receptor 2 (apoER2), and meg alin/gp330. In this context, the main objective of the present study was to better understand the contributions of LRP and LDL-R to the in vivo neurot rophic effects of apoE. For this purpose, apoE-deficient and receptor-assoc iated protein (RAP)deficient mice were infused with recombinant apoE3, RAP, or saline. Infusion of apoE3 into apoE-deficient mice resulted in ameliora tion of degenerative alterations of pyramidal neurons, but had no effect on somatostatin-producing interneurons. In contrast, infusion of apoE3 into R AP-deficient mice resulted in amelioration of degenerative alterations of s omatostatin-producing interneurons. LRP and LDL-R levels were significantly reduced in RAP-deficient mice, but significantly increased in the apoE-def icient mice. In contrast, levels of apoE were reduced in the RAP-eficient m ice compared to wildtype controls, suggesting that neurotrophic effects of apoE3 in the RAP-deficient mice were related to a combined deficit in endog enous apoE and selected apoE receptors. Furthermore, in apoE-deficient mice , infusion of apoE3 had a neurotrophic effect on somatostatin-producing int erneurons only when combined with RAP, suggesting that increased expression of apoE receptors in apoE-deficient mice prevented apoE from rescuing soma tostatin-producing neurons. This study supports the contention that some of the in vivo neurotrophic effects of apoE are mediated by LRP and LDL-R and that a critical balance between levels of apoE and its receptors is necess ary for the differential neurotrophic effects to appear. (C) 2001 Academic Press.