Specific regional transcription of apolipoprotein E in human brain neurons

In central nervous system injury and disease, apolipoprotein E (APOE, gene; apoE, protein) might be involved in neuronal injury and death indirectly t hrough extracellular effects and/or more directly through intracellular eff ects on neuronal metabolism. Although intracellular effects could clearly b e mediated by neuronal uptake of extracellular apoE, recent experiments in injury models in normal rodents and in mice transgenic for the human APOE g ene suggest the additional possibility of intraneuronal synthesis. To exami ne whether APOE might be synthesized by human neurons, we performed in situ hybridization on paraffin-embedded and frozen brain sections from three no ndemented controls and five Alzheimer's disease (AD) patients using digoxig enin-labded antisense and sense cRNA probes to human APOE, Using the antise nse APOE probes, we found the expected strong hybridization signal in glial cells as well as a generally fainter signal in selected neurons in cerebra l cortex and hippocampus, In hippocampus, many APOE mRNA-containing neurons were observed in sectors CA1 to CA4 and the granule cell layer of the dent ate gyrus, in these regions, APOE mRNA containing neurons could be observed adjacent to nonhybridizing neurons of the same cell class. APOE mRNA trans cription in neurons is regionally specific. In cerebellar cortex, APOE mRNA was seen only in Bergmann glial cells and scattered astrocytes but not in Purkinje cells or granule cell neurons. ApoE immunocytochemical localizatio n in semi-adjacent sections supported the selectivity of APOE transcription . These results demonstrate the expected result that APOE mRNA is transcrib ed and expressed in glial cells in human brain. The important new finding i s that APOE mRNA is also transcribed and expressed in many neurons in front al cortex and human hippocampus but not in neurons of cerebellar cortex fro m the same brains, This regionally specific human APOE gene expression sugg ests that synthesis of apoE might play a role in regional vulnerability of neurons in AD. These results also provide a direct anatomical context for h ypotheses proposing a role for apoE isoforms on neuronal cytoskeletal stabi lity and metabolism.