APOE genotype affects the pre‐synaptic compartment of glutamatergic nerve terminals
Open accessAbstract
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.
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Previous research on humanized APOE mice showed reduced glutamine levels and reduced capacity to incorporate glutamate into the brain of APOE 4TR mice, while glutamate transporters were not significantly changed.
“Previous research on humanized APOE mice showed reduced glutamine levels, and reduced capacity to incorporate glutamate into the brain of APOE 4TR mice, while glutamate transporters were not significantly changed (Dumanis et al., 2013).”
From APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes (2022) · cites this paper as Dumanis et al., 2013
The Results section reports lower glutamate levels and lower incorporation of a glucose-derived 13C label into glutamate in APOE-ε4 TR mice, but it reports significantly higher—not reduced—glutamine levels. The Abstract says glutamate uptake transporters were unchanged; it also reports an increase in the vesicular glutamate transporter VGLUT1, so the claim is too broad about transporters. Page numbers were not provided in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredApoE is involved in the modulation of glutamate transport and metabolism.
“ApoE is also involved in the modulation of glutamate transport and metabolism [128]”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [128]
These findings suggest a reduced ability of presynaptic ApoE4 neurons to convert glutamine to glutamate and a compensatory increase in vesicular glutamate loading.
“suggesting a reduced ability of presynaptic ApoE4 neurons to convert glutamine to glutamate and a compensatory increase in vesicular glutamate loading [75].”
From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [75]
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Cites
Localization of neuronal and glial glutamate transporters
Rothstein, J. D., Martin, L. J., Levey, A. I., Dykes‐Hoberg, M., Jin, L., Wu, D. M., Nash, N. R., & Kuncl, R. W. (1994) · Neuron · doi:10.1016/0896-6273(94)90038-8 · Cited by 1,703 · see citing works
Distinct patterns of brain activity in young carriers of the <i>APOE</i> -ε4 allele
Filippini, N., MacIntosh, B. J., Hough, M. G., Goodwin, G. M., Frisoni, G. B., Smith, S. M., Matthews, P. M., Beckmann, C. F., & Mackay, C. E. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811879106 · Cited by 1,613 · see citing works
Reiman, E. M., Caselli, R. J., Yun, L. S., Chen, K., Bandy, D., Minoshima, S., Thibodeau, S. N., & Osborne, D. (1996) · New England Journal of Medicine · doi:10.1056/nejm199603213341202 · Cited by 1,366 · see citing works
Primary structure and functional characterization of a high-affinity glutamate transporter
Kanai, Y., & Hediger, M. A. (1992) · Nature · doi:10.1038/360467a0 · Cited by 1,339 · see citing works
Apolipoprotein E controls cerebrovascular integrity via cyclophilin A
Bell, R. D., Winkler, E. A., Singh, I., Sagare, A. P., Deane, R., Wu, Z., Holtzman, D. M., Betsholtz, C., Armulik, A., Sallstrom, J., et al. (2012) · Nature · doi:10.1038/nature11087 · Cited by 1,293 · see citing works
Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia
Reiman, E. M., Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., Osborne, D., Saunders, A. M., & Hardy, J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2635903100 · Cited by 977 · see citing works
Takamori, S., Rhee, J. S., Rosenmund, C., & Jahn, R. (2000) · Nature · doi:10.1038/35025070 · Cited by 862 · see citing works
Small, G. W. (1995) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.1995.03520360056039 · Cited by 604 · see citing works
Sullivan, P. M., Mezdour, H., Aratani, Y., Knouff, C., Najib, J., Reddick, R. L., Quarfordt, S. H., & Maeda, N. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.29.17972 · Cited by 575 · see citing works
Wojcik, S. M., Rhee, J. S., Herzog, É., Sigler, A., Jahn, R., Takamori, S., Brose, N., & Rosenmund, C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401764101 · Cited by 510 · see citing works
Reiman, E. M., Caselli, R. J., Chen, K., Alexander, G. E., Bandy, D., & Frost, J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.061509598 · Cited by 467 · see citing works
Lebon, V., Petersen, K. F., Cline, G. W., Shen, J., Mason, G. F., Dufour, S., Behar, K. L., Shulman, G. I., & Rothman, D. L. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-05-01523.2002 · Cited by 371 · see citing works
Chen, Y., Durakoglugil, M. S., Xian, X., & Herz, J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914984107 · Cited by 368 · see citing works
Presynaptic Regulation of Quantal Size by the Vesicular Glutamate Transporter VGLUT1
Wilson, N. R., Kang, J., Hueske, E. V., Leung, T., Varoqui, H., Murnick, J. G., Erickson, J. D., & Liu, G. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.3003-04.2005 · Cited by 335 · see citing works
Andrews-Zwilling, Y., Bien-Ly, N., Xu, Q., Li, G., Bernardo, A., Yoon, S. Y., Zwilling, D., Yan, T. X., Chen, L., & Huang, Y. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4040-10.2010 · Cited by 326 · see citing works
Nishitsuji, K., Hosono, T., Nakamura, T., Bu, G., & Michikawa, M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.225532 · Cited by 275 · see citing works
Epidemiological Studies of the Effect of Stroke on Incident Dementia: A Systematic Review
Savva, G. M., Stephan, B. C. M., & the Alzheimer’s Society Vascular Dementia Systematic Review Group (2010) · Stroke · doi:10.1161/strokeaha.109.559880 · Cited by 257 · see citing works
Sullivan, P. M., Mezdour, H., Quarfordt, S. H., & Maeda, N. (1998) · Journal of Clinical Investigation · doi:10.1172/jci2673 · Cited by 254 · see citing works
VGLUTs: ‘Exciting’ times for glutamatergic research?
Takamori, S. (2006) · Neuroscience Research · doi:10.1016/j.neures.2006.04.016 · Cited by 249 · see citing works
Meta-Analysis of APOE 4 Allele and Outcome after Traumatic Brain Injury
Zhou, W., Xu, D., Peng, X., Zhang, Q., Jia, J., & Crutcher, K. A. (2008) · Journal of Neurotrauma · doi:10.1089/neu.2007.0489 · Cited by 241 · see citing works
ApoE4 Decreases Spine Density and Dendritic Complexity in Cortical Neurons<i>In Vivo</i>
Dumanis, S. B., Tesoriero, J. A., Babus, L. W., Nguyen, M. T., Trotter, J. H., Ladu, M. J., Weeber, E. J., Turner, R. S., Xu, B., Rebeck, G. W., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.4026-09.2009 · Cited by 220 · see citing works
Self-citationA Single Vesicular Glutamate Transporter Is Sufficient to Fill a Synaptic Vesicle
Daniels, R. W., Collins, C. A., Chen, K., Gelfand, M. V., Featherstone, D. E., & DiAntonio, A. (2006) · Neuron · doi:10.1016/j.neuron.2005.11.032 · Cited by 194 · see citing works
Laake, J. H., Slyngstad, T. A., Haug, F. Š., & Ottersen, O. P. (1995) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1995.65020871.x · Cited by 193 · see citing works
Ji, Y., Gong, Y., Gan, W., Beach, T., Holtzman, D. M., & Wisniewski, T. (2003) · Neuroscience · doi:10.1016/j.neuroscience.2003.08.007 · Cited by 189 · see citing works
Burt, T., Agan, B., Marconi, V., He, W., Kulkarni, H., Mold, J. E., Cavrois, M., Huang, Y.-D., Mahley, R., Dolan, M., et al. (2008) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0803526105 · Cited by 185 · see citing works
Khandelwal, P. J., Herman, A. M., Hoe, H., Rebeck, G. W., & Moussa, C. E. H. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr091 · Cited by 182 · see citing works
Self-citationGrootendorst, J., Bour, A., Vogel, E., Kelche, C., Sullivan, P. M., Dodart, J.-C., Bales, K., & Mathis, C. (2005) · Behavioural Brain Research · doi:10.1016/j.bbr.2004.09.019 · Cited by 148 · see citing works
Bour, A., Grootendorst, J., Vogel, E., Kelche, C., Dodart, J.-C., Bales, K., Moreau, P.-H., Sullivan, P. M., & Mathis, C. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.05.008 · Cited by 141 · see citing works
Impaired recycling of apolipoprotein E4 is associated with intracellular cholesterol accumulation
Heeren, J., Grewal, T., Laatsch, A., Becker, N., Rinninger, F., Rye, K.-A., & Beisiegel, U. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m409324200 · Cited by 139 · see citing works
Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology.
Wang, C., Wilson, W. A., Moore, S. D., Mace, B. E., Maeda, N., Schmechel, D. E., & Sullivan, P. M. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.10.013 · Cited by 138 · see citing works
Kinetics and localization of brain phosphate activated glutaminase
Kvamme, E., Torgner, I. A., & Roberg, B. (2001) · Journal of Neuroscience Research · doi:10.1002/jnr.10041 · Cited by 134 · see citing works
ApoE isoform affects LTP in human targeted replacement mice
Trommer, B. L., Shah, C., Yun, S. H., Gamkrelidze, G., Pasternak, E. S., Ye, G. L., Sotak, M., Sullivan, P. M., Pasternak, J. F., & LaDu, M. J. (2004) · NeuroReport · doi:10.1097/00001756-200412030-00020 · Cited by 124 · see citing works
Apolipoprotein E, Amyloid, and Alzheimer Disease
Bales, K. R. (2002) · Molecular Interventions · doi:10.1124/mi.2.6.363 · Cited by 113 · see citing works
APOE related alterations in cerebral activation even at college age
Scarmeas, N. (2005) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.2004.053645 · Cited by 97 · see citing works
Changes in the cellular distribution of glutamine synthetase in Alzheimer's disease
Robinson, S. R. (2001) · Journal of Neuroscience Research · doi:10.1002/jnr.10057 · Cited by 96 · see citing works
Пономарева, Н. В., Коровайцева, Г. И., & Rogaev, E. I. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.12.019 · Cited by 93 · see citing works
Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by 15N NMR
Kanamori, K., Ross, B. D., & Kondrat, R. W. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.70031304.x · Cited by 89 · see citing works
ApoE isoform-dependent changes in hippocampal synaptic function
Korwek, K. M., Trotter, J. H., LaDu, M. J., Sullivan, P. M., & Weeber, E. J. (2009) · Molecular Neurodegeneration · doi:10.1186/1750-1326-4-21 · Cited by 89 · see citing works
Glutamate transporter expression and function in human glial progenitors
Maragakis, N. J., Dietrich, J., Wong, V., Xue, H., Mayer‐Pröschel, M., Rao, M. S., & Rothstein, J. D. (2003) · Glia · doi:10.1002/glia.10310 · Cited by 87 · see citing works
ApoE isoform-specific effects on LTP: blockade by oligomeric amyloid-β1–42
Trommer, B. L., Shah, C., Yun, S. H., Gamkrelidze, G., Pasternak, E. S., Blaine Stine, W., Manelli, A., Sullivan, P., Pasternak, J. F., & LaDu, M. J. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.08.011 · Cited by 82 · see citing works
Glutamate Metabolizing Enzymes in Prefrontal Cortex of Alzheimer’s Disease Patients
Burbaeva, G. S., Бокша, И. С., Терешкина, Е. Б., Savushkina, O. K., Starodubtseva, L. I., & Turishcheva, M. S. (2005) · Neurochemical Research · doi:10.1007/s11064-005-8654-x · Cited by 79 · see citing works
Altschuler, R. A., Monaghan, D. T., Haser, W. G., et al. (1985) · Brain Research · doi:10.1016/0006-8993(85)90681-x · Cited by 72 · see citing works
Kariv-Inbal, Z., Yacobson, S., Berkecz, R., Péter, M., Janáky, T., Lütjohann, D., Broersen, L., Hartmann, T., & Michaelson, D. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2011-111265 · Cited by 70 · see citing works
Shashidharan, P., Huntley, G. W., Meyer, T., Morrison, J. H., & Plaitakis, A. (1994) · Brain Research · doi:10.1016/0006-8993(94)90819-2 · Cited by 59 · see citing works
Emergence of a seizure phenotype in aged apolipoprotein epsilon 4 targeted replacement mice
Hunter, J. M., Cirrito, J. R., Restivo, J. L., Kinley, R. D., Sullivan, P. M., Holtzman, D. M., Koger, D., Delong, C., Lin, S., Zhao, L., et al. (2012) · Brain Research · doi:10.1016/j.brainres.2012.05.048 · Cited by 45 · see citing works
Yelamanchili, S. V., Pendyala, G., Brunk, I., Darna, M., Albrecht, U., & Ahnert‐Hilger, G. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m600378200 · Cited by 45 · see citing works
Expression of EAAT2 in neurons and protoplasmic astrocytes during human cortical development
DeSilva, T. M., Borenstein, N. S., Volpe, J. J., Kinney, H. C., & Rosenberg, P. A. (2012) · The Journal of Comparative Neurology · doi:10.1002/cne.23130 · Cited by 43 · see citing works
Time of Day-dependent Sorting of the Vesicular Glutamate Transporter to the Plasma Membrane
Darna, M., Schmutz, I., Richter, K., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805480200 · Cited by 31 · see citing works
Cleavage of the vesicular glutamate transporters under excitotoxic conditions
Lobo, A. C., Gomes, J. R., Catarino, T., Mele, M., Fernandez, P., Inácio, A. R. L., Bahr, B. A., Santos, A. E., Wieloch, T. W., Carvalho, A. L., et al. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.07.010 · Cited by 22 · see citing works
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“Studies in ApoE4 targeted replacement (TR) mice have shown decreased levels of glutamate, increased levels of glutamine (the precursor of glutamate), and a late increase in vesicular glutamate transporter 1 (vglut1), suggesting a reduced ability of presynaptic ApoE4 neurons to convert glutamine to glutamate and a comp…”
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- Authors
- Dumanis, S. B., DiBattista, A. M., Miessau, M., Moussa, C. E. H., & Rebeck, G. W.
- Affiliations
- Georgetown University Medical Center (US)
- Corresponding author
- Rebeck, G. William
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2012-09-28
- Volume
- 124
- Issue
- 1
- Pages
- 4-14
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- PMC
- PMC3509249
- OpenAlex
- W2093187894
- Cited by
- 55
- References
- 49
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 2 · 2022: 5 · 2021: 4 · 2020: 8 · 2019: 4 · 2018: 3 · 2017: 6 · 2016: 4 · 2015: 3 · 2014: 8 · 2013: 3 · 2012: 1
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation
- National Institutes of Health
- National Institute on Aging (P01AG030128, AG 30378, R01AG035379, K01AG030378)
- National Institute of Neurological Disorders and Stroke (T32NS041231)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- apolipoprotein E, APOE ε4, glutamate-glutamine cycle, VGLUT1, glutaminase, glutamate synthesis, glutamine, dendritic spines, glutamine synthetase, Alzheimer's disease risk, neurodegeneration
- MeSH terms
- Animals, Apolipoproteins E, Brain, Carbon Isotopes, Gene Expression Regulation, Glutaminase, Humans, Mice, Inbred C57BL, Mice, Transgenic, Magnetic Resonance Spectroscopy, Tritium, Presynaptic Terminals, Glutamic Acid, Vesicular Glutamate Transport Protein 1, Mice, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2
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