We have investigated the synthesis and transport of apoE, the major apolipoprotein of the central nervous system, in the retina of the living rabbit. Four hours after the injection of [ ]Met/ Cys-labeled apoE is rapidly transported into the optic nerve and its terminals in the lateral geniculate and superior colliculus within 3-6 h in two distinguishable vesicular compartments. Mü ller glia in cell culture also synthesize and secrete apoE. Taken together, these results suggest that apoE is synthesized by Mü ller glia and secreted into the vitreous. ApoE is also internalized by retinal ganglion cells and/or synthesized by these cells and rapidly transported into the optic nerve and brain as an intact molecule. We discuss the possible roles of retinal apoE in neuronal dynamics.ApoE, a 36-kDa glycoprotein, is a component of a number of circulating plasma lipoproteins, including very low density lipoproteins, high density lipoproteins, and chylomicron remnants (1). Its primary function appears to be that of a recognition ligand for the receptor-specific removal of cholesteryl ester-rich lipoproteins from the circulation (2, 3). It also plays a role in local transport of cholesterol, as seen in nerves of both peripheral (4, 5) and central nervous systems (reviewed in Ref. 6) and has been implicated in mediating immune responses and cell proliferation, processes that may not be related to its association with lipid (for review, see Ref. 1).In plasma, apoE transports lipoproteins containing cholesterol, triglycerides and other lipids to various cells via binding to the low density lipoprotein (LDL) 1 receptor (7) or the LDL receptor-related protein (LRP)/␣ 2 -macroglobulin receptor (8, 9). In the central nervous system, apoE is primarily synthesized by the major glial cell, the astrocyte, in rodents and humans (10, 11) and is found in significant quantities in the cerebrospinal fluid (10). Since apolipoprotein B, the other molecule that can mediate the internalization of lipoproteins via association with the LDL receptor, is not synthesized in the central nervous system (reviewed in Ref. 6), it is highly likely that apoE plays a major role in cholesterol and lipid transport in this compartment.We have employed the in vivo rabbit retina to probe the synthesis, intracellular transport, and metabolism of central nervous system proteins including kinesin, the motor for anterograde rapid transport (12, 13), and the -amyloid precursor protein (APP) (14, 15). Since it has been shown recently that individuals having the ⑀4 allele of apoE are at high risk for Alzheimer's disease (16), we decided to use this widely accepted model of normal adult retinal protein synthesis and metabolism (e.g. Refs. 17 and 18) to examine the synthesis and transport of apoE. In this report, we present evidence, obtained by the injection of [ 35 S]methionine/cysteine into the vitreous chamber that overlies the retina, that apoE is synthesized in significant quantities in vivo by rabbit Mü ller cells, the predominant glial cell of the retina. ApoE ...