Specific Regional Transcription of Apolipoprotein E in Human Brain Neurons

Abstract

In central nervous system injury and disease , apolipoprotein E (APOE, gene; apoE , protein) might be involved in neuronal injury and death indirectly through extracellular effects and/or more directly through intracellular effects on neuronal metabolism. Although intracellular effects could clearly be mediated by neuronal uptake of extracellular apoE , recent experiments in injury models in normal rodents and in mice transgenic for the human APOE gene suggest the additional possibility of intraneuronal synthesis. To examine whether APOE might be synthesized by human neurons , we performed in situ hybridization on paraffin-embedded and frozen brain sections from three nondemented controls and five Alzheimer's disease (AD) patients using digoxigenin-labeled antisense and sense cRNA probes to human APOE. Using the antisense APOE probes , we found the expected strong hybridization signal in glial cells as well as a generally fainter signal in selected neurons in cerebral cortex and hippocampus. In hippocampus, many APOE mRNA-containing neurons were observed in sectors CA1 to CA4 and the granule cell layer of the dentate gyrus. In these regions , APOE mRNA containing neurons could be observed adjacent to nonhybridizing neurons of the same cell class. APOE mRNA transcription 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 localization in semi-adjacent sections supported the selectivity of APOE transcription. These results demonstrate the expected result that APOE mRNA is transcribed and expressed in glial cells in human brain. The important new finding is that APOE mRNA is also transcribed and expressed in many neurons in frontal cortex and human hippocampus but not in neurons of cerebellar cortex from the same brains. This regionally specific human APOE gene expression suggests that synthesis of apoE might play a role in regional vulnerability of neurons in AD. These results also provide a direct anatomical context for hypotheses proposing a role for apoE isoforms on neuronal cytoskeletal stability and metabolism. (Am J Pathol 1999, 154:601-611) Apolipoprotein E (apoE) is a major cholesterol transport protein expressed in two separate compartments: peripheral tissues and nervous system.

Prominent Axonopathy and Disruption of Axonal Transport in Transgenic Mice Expressing Human Apolipoprotein E4 in Neurons of Brain and Spinal Cord

“…33,34 Moreover, in situ hybridization of human brain sections conclusively demonstrated ApoE mRNA in neurons. 35 Taken together these results suggest that besides its well-known synthesis by glia cells and its role in lipid transport and metabolism, not only uptake but also synthesis of ApoE by neurons might be important. Interestingly, the brain regions expressing ApoE in neurons seemed most vulnerable to the development of neurofibrillary pathology, 36 raising the possibility that the neuronal expression pattern of human ApoE might be important in the pathogenesis of AD.…”

“…Surprisingly, no neuronal loss was established, although some neurons with loss of Nissl substance and increased AT8 immunoreactivity were observed. In this context, the observed impairment of axonal transport in AD neurons, their loss of polarity and subsequent degeneration, 41,42 and an increased vulnerability to neuronal death in those brain regions that express ApoE in neurons, 35,36 is of special interest. Although great care should be taken in extrapolating re- sults from mouse models to humans, it is possible to speculate that the axonal degeneration we observe in our mice represents some form of neuronal degeneration.…”

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

“…However, CNS neurons express apoE under physiological and pathological conditions (101)(102)(103)(104)(105)(106)(107)(108)(109)(110). ApoE mRNA is found in cortical and hippocampal neurons in humans (106) and in transgenic mice expressing human apoE under the control of the human apoE promoter (109). Treatment with kainic acid induces apoE synthesis in hippocampal neurons in rats (111), and apoE is expressed in neurons in cerebral infarct patients (112).…”

Impairments in spatial memory retention of GFAP-apoE4 female mice

“…Most synthesis of apoE in the brain takes place in glial cells, in particular astrocytes. However, neurons are also able to generate apoE, particularly following injury [1,5,8,21,22]. In addition, apoE can be secreted from astrocytes and be taken up by neurons.…”