Synthesis and processing of apolipoprotein E in human brain cultures

Apolipoprotein E (apoE) plays a role in the distribution of lipid within ma ny organs and cell types in the human body, including neurons and astrocyte s of the central nervous system (CNS). The apoE4 isoform is also a genetic risk factor for late onset Alzheimer's disease (AD). However, the mechanism by which apoE is involved in AD is largely unknown. In order to understand how apoE is involved in the distribution of lipid in the CNS, we sought to investigate not only the origin of intraneuronal apoE, but the pathway by which it is processed once synthesized. We have established that human neur ons can synthesize apoE in the presence of astrocytes, and that intracellul ar neuronal apoE is processed through the rough endoplasmic reticulum, golg i, and CD63-positive lysosomes where it may be stored before secretion. Our results also suggest that apoE synthesis is regulated by a feedback mechan ism, controlled by the neuron itself. This regulatory mechanism may be esse ntial to the maintenance of neuronal cholesterol concentrations and in turn membrane stability. GLIA 33:298-305, 2001. (C) 2001 Wiley-Liss, Inc.