title: APOE genotype affects the pre-synaptic compartment of glutamatergic nerve terminals.
abstract: Apolipoprotein E (APOE) genotype affects outcomes of Alzheimer's disease and other conditions of brain damage. Using APOE knock-in mice, we have previously shown that APOE-ε4 Targeted Replacement (TR) mice have fewer dendritic spines and reduced branching in cortical neurons. As dendritic spines are post-synaptic sites of excitatory neurotransmission, we used APOE TR mice to examine whether APOE genotype affected the various elements of the glutamate-glutamine cycle. We found that levels of glutamine synthetase and glutamate uptake transporters were unchanged among the APOE genotypes. However, compared with APOE-ε3 TR mice, APOE-ε4 TR mice had decreased glutaminase levels (18%, p < 0.05), suggesting decreased conversion of glutamine to glutamate. APOE-ε4 TR mice also had increased levels of the vesicular glutamate transporter 1 (20%, p < 0.05), suggesting that APOE genotype affects pre-synaptic terminal composition. To address whether these changes affected normal neurotransmission, we examined the production and metabolism of glutamate and glutamine at 4-5 months and 1 year. Using high-frequency (13)C/(1)H nuclear magnetic resonance spectroscopy, we found that APOE-ε4 TR mice have decreased production of glutamate and increased levels of glutamine. These factors may contribute to the increased risk of neurodegeneration associated with APOE-ε4, and also act as surrogate markers for Alzheimer's disease risk.
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Sonya B
authors.initials: SB
authors.lastname: Dumanis
authors.forename: Amanda M
authors.initials: AM
authors.lastname: DiBattista
authors.forename: Matthew
authors.initials: M
authors.lastname: Miessau
authors.forename: Charbel E H
authors.initials: CE
authors.lastname: Moussa
authors.forename: G William
authors.initials: GW
authors.lastname: Rebeck
mesh_terms: D000818:Animals; D053329:Apolipoprotein E2 / Q000235:genetics; D053318:Apolipoprotein E3 / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics*; D001921:Brain / Q000166:cytology*; D002247:Carbon Isotopes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D018698:Glutamic Acid / Q000378:metabolism*; D005972:Glutaminase / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017729:Presynaptic Terminals / Q000378:metabolism*; D014316:Tritium / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D002247:Carbon Isotopes; D050598:Vesicular Glutamate Transport Protein 1; D014316:Tritium; D018698:Glutamic Acid; D005972:Glutaminase