Glial fibrillary acidic protein-apolipoprotein E (apoE) transgenic mice: astrocyte-specific expression and differing biological effects of astrocyte-secreted apoE3 and apoE4 lipoproteins.

Sun, Yuling; Wu, Shan; Bu, Guojun; Onifade, Moyosore K.; Patel, Shilen N.; LaDu, Mary Jo; Fagan, Anne M.; Holtzman, David M.

doi:10.1523/jneurosci.18-09-03261.1998

Cited by 213Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsBarrier Structure and Function Studies

Glial fibrillary acidic protein-apolipoprotein E (apoE) transgenic mice: astrocyte-specific expression and differing biological effects of astrocyte-secreted apoE3 and apoE4 lipoproteins.

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Sun, Yuling, Wu, Shan, Bu, Guojun, Onifade, Moyosore K., Patel, Shilen N., LaDu, Mary Jo, Fagan, Anne M., Holtzman, David M.·1998·The Journal of Neuroscience

DOI 10.1523/jneurosci.18-09-03261.1998PMC PMC6792658

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Abstract

The ε4 allele of apolipoprotein E (apoE) is associated with increased risk for Alzheimer’s disease (AD) and poor outcome after brain injury. In the CNS, apoE is expressed by glia, predominantly astrocytes. To define the potential biological functions of different human apoE isoforms produced within the brain, transgenic mice were generated in which human apoE3 and apoE4 expression is under control of the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter. These animals were then bred back to apoE knock-out mice. Human apoE protein is found within astrocytes and the neuropil throughout development and into the adult period, as assessed by immunocytochemistry and immunoblot analysis in several GFAP-apoE3 and E4 lines. Cultured astrocytes from these mice secrete apoE3 and apoE4 in lipoproteins that are high-density lipoprotein-like in size. When primary hippocampal neurons are grown in the presence of astrocyte monolayers derived from these transgenic mice, there is significantly greater neurite outgrowth from neurons grown in the presence of apoE3-secreting astrocytes compared with apoE4-secreting or apoE knock-out astrocytes. These effects are not dependent on direct astrocyte–neuron contact and appear to require the low-density lipoprotein receptor-related protein. These data suggest that astrocyte-secreted, apoE3-containing lipoproteins have different biological effects than apoE4-containing lipoproteins. In addition to providing information regarding the role of astrocyte-secreted apoE lipoproteins in the normal brain, these animals will also be useful in models of both AD and CNS injury.

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Most studies have demonstrated that apoE3 isoform promotes neurite outgrowth in primary embryonic and adult cortical neurons, as well as neuronal cell lines.
“Most studies have demonstrated that apoE3 isoform promotes neurite outgrowth in primary embryonic and adult cortical neurons, as well as neuronal cell lines (Nathan et al., 1994; 2002; Sun et al., 1998).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Sun et al., 1998
The Results report greater neurite outgrowth in embryonic day 19 primary hippocampal neurons exposed to apoE3-expressing astrocytes, and summarize previous findings in neuronal cell lines. The paper does not establish the claimed effect in primary embryonic or adult cortical neurons; its own primary-neuron experiments used embryonic hippocampal neurons. (LLM, conf=0.88)
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Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, Pericak-Vance M A, Goldgaber D, Roses AD (1993) In- creased amyloid ␤-peptide deposition in cerebral cortex as a conse- quence of apolipoprotein genotype in late-onset Alzheimer disease. Proc Natl Acad Sci USA 90:9649 -9653.
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Apolipoprotein E: Far More Than a Lipid Transport Protein
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Distinct patterns of brain activity in young carriers of the APOE -ε4 allele
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The role of apolipoprotein E in Alzheimer's disease
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Glial Fibrillary Acidic Protein: GFAP-Thirty-One Years (1969–2000)
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Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease
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Brain Cholesterol: Long Secret Life Behind a Barrier
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Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease
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Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease
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ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
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Cholesterol metabolism in neurons and astrocytes
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Apolipoprotein E is essential for amyloid deposition in the APP V717F transgenic mouse model of Alzheimer's disease
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ApoE and Clusterin Cooperatively Suppress Aβ Levels and Deposition
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Cholesterol homeostasis and function in neurons of the central nervous system
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Role of retinoid signalling in the adult brain
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Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease
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Apolipoprotein E
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Expression of Human Apolipoprotein E3 or E4 in the Brains ofApoe−/−Mice: Isoform-Specific Effects on Neurodegeneration
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Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer's disease
Holtzman, D. M., Bales, K. R., Wu, S., Bhat, P., Parsadanian, M., Fagan, A. M., Chang, L. K., Sun, Y., & Paul, S. M. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6179 · Cited by 349 · see citing works
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Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress
Dong, H., Goico, B., Martin, M., Csernansky, C. A., Bertchume, A., & Csernansky, J. G. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.05.040 · Cited by 342 · see citing works
Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β
Koffie, R. M., Hashimoto, T., Tai, H.-C., Kay, K. R., Serrano-Pozo, A., Joyner, D., Hou, S., Kopeikina, K. J., Frosch, M. P., Lee, V. M., et al. (2012) · Brain · doi:10.1093/brain/aws127 · Cited by 327 · see citing works
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APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease
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Human and Murine ApoE Markedly Alters Aβ Metabolism before and after Plaque Formation in a Mouse Model of Alzheimer's Disease
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Lipid droplets in the nervous system
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Role of Tissue Plasminogen Activator Receptor LRP in Hippocampal Long-Term Potentiation
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BDNF Blocks Caspase-3 Activation in Neonatal Hypoxia–Ischemia
Han, B. H., D'Costa, A. P., Back, S. A., Parsadanian, M., Patel, S., Shah, A. R., Gidday, J. M., Srinivasan, A. N., Deshmukh, M., & Holtzman, D. M. (2000) · Neurobiology of Disease · doi:10.1006/nbdi.1999.0275 · Cited by 267 · see citing works
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Plasma biomarkers of astrocytic and neuronal dysfunction in early‐ and late‐onset Alzheimer's disease
Elahi, F. M., Casaletto, K. B., Joie, R. L., Walters, S. M., Harvey, D. J., Wolf, A. A., Edwards, L., Contreras, W. R., Karydas, A., Cobigo, Y., et al. (2019) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2019.09.004 · Cited by 250 · see citing works
Glymphatic distribution of CSF-derived apoE into brain is isoform specific and suppressed during sleep deprivation
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Apolipoprotein E: Diversity of Cellular Origins, Structural and Biophysical Properties, and Effects in Alzheimer's Disease
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Expression of Human Apolipoprotein E4 in Neurons Causes Hyperphosphorylation of Protein Tau in the Brains of Transgenic Mice
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Unique Lipoproteins Secreted by Primary Astrocytes From Wild Type, apoE (−/−), and Human apoE Transgenic Mice
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The evolution of Alzheimer disease, the reproductive schedule, and apoE isoforms☆
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Lipoproteins in the Central Nervous System
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Apolipoprotein E4 Forms a Molten Globule
Morrow, J. A., Hatters, D. M., Lu, B., Höchtl, P., Oberg, K. A., Rupp, B., & Weisgraber, K. H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204898200 · Cited by 204 · see citing works
Glial Cell Aquaporin-4 Overexpression in Transgenic Mice Accelerates Cytotoxic Brain Swelling
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Electromagnetic Controlled Cortical Impact Device for Precise, Graded Experimental Traumatic Brain Injury
Brody, D. L., Donald, C. M., Kessens, C. C., Yuede, C. M., Parsadanian, M., Spinner, M., Kim, E., Schwetye, K. E., Holtzman, D. M., & Bayly, P. V. (2007) · Journal of Neurotrauma · doi:10.1089/neu.2006.0011 · Cited by 197 · see citing works
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Differential effects of the APOE genotype on brain function across the lifespan
Filippini, N., Ebmeier, K. P., MacIntosh, B. J., Trachtenberg, A. J., Frisoni, G. B., Wilcock, G. K., Beckmann, C. F., Smith, S. M., Matthews, P. M., & Mackay, C. E. (2010) · NeuroImage · doi:10.1016/j.neuroimage.2010.08.009 · Cited by 195 · see citing works
Multifaceted roles of APOE in Alzheimer disease
Jackson, R. J., Hyman, B. T., & Serrano-Pozo, A. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00988-2 · Cited by 193 · see citing works
A Self-Destructive Nanosweeper That Captures and Clears Amyloid β-Peptides
Luo, Q., Lin, Y.-X., Yang, P.-P., Wang, Y., Qi, G.-B., Qiao, Z.-Y., Li, B.-N., Zhang, K., Zhang, J.-P., Wang, L., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04255-z · Cited by 191 · see citing works
Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and Alzheimer's disease patients
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
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Androgens Protect against Apolipoprotein E4-Induced Cognitive Deficits
Raber, J., Bongers, G., LeFevour, A., Buttini, M., & Mucke, L. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-12-05204.2002 · Cited by 187 · see citing works
Purification and characterization of astrocyte-secreted apolipoprotein E and J-containing lipoproteins from wild-type and human apoE transgenic mice
DeMattos, R. B., Brendza, R. P., Heuser, J. E., Kierson, M., Cirrito, J. R., Fryer, J., Sullivan, P. M., Fagan, A. M., Han, X., & Holtzman, D. M. (2001) · Neurochemistry International · doi:10.1016/s0197-0186(01)00049-3 · Cited by 180 · see citing works
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Formation and function of apolipoprotein E-containing lipoproteins in the nervous system.
Vance, J., & Hayashi, H. (2010) · Biochimica et Biophysica Acta · doi:10.1016/j.bbalip.2010.02.007 · Cited by 185 · see citing works
Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease
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Neuroplasticity in Alzheimer's disease
Teter, B., & Ashford, J. W. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10441 · Cited by 170 · see citing works
The role of apolipoprotein E in Alzheimer’s disease, acute brain injury and cerebrovascular disease: evidence of common mechanisms and utility of animal models
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Apolipoprotein E and cholesterol in aging and disease in the brain
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Behavioral phenotyping of GFAP-ApoE3 and -ApoE4 transgenic mice: ApoE4 mice show profound working memory impairments in the absence of Alzheimer’s-like neuropathology.
Hartman, R. E., Wozniak, D. F., Nardi, A., Olney, J. W., Sartorius, L., & Holtzman, D. M. (2001) · Experimental Neurology · doi:10.1006/exnr.2001.7715 · Cited by 157 · see citing works
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Astrocytic ApoE reprograms neuronal cholesterol metabolism and histone-acetylation-mediated memory
Li, X., Zhang, J., Li, D., He, C., He, K., Xue, T., Wan, L., Zhang, C., & Liu, Q. (2021) · Neuron · doi:10.1016/j.neuron.2021.01.005 · Cited by 165 · see citing works
A Synthetic Peptide Blocking the Apolipoprotein E/β-Amyloid Binding Mitigates β-Amyloid Toxicity and Fibril Formation in Vitro and Reduces β-Amyloid Plaques in Transgenic Mice
Sadowski, M., Pankiewicz, J., Scholtzova, H., Ripellino, J. A., Li, Y., Schmidt, S. D., Mathews, P. M., Fryer, J. D., Holtzman, D. M., Sigurdsson, E. M., et al. (2004) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63355-x · Cited by 154 · see citing works
Self-citation
Apolipoprotein E4 inhibits, and apolipoprotein E3 promotes neurite outgrowth in cultured adult mouse cortical neurons through the low-density lipoprotein receptor-related protein
Nathan, B. P., Jiang, Y., Wong, G. K., Shen, F., Brewer, G. J., & Struble, R. G. (2002) · Brain Research · doi:10.1016/s0006-8993(01)03367-4 · Cited by 169 · see citing works
Apolipoprotein E and β-amyloid levels in the hippocampus and frontal cortex of Alzheimer's disease subjects are disease-related and apolipoprotein E genotype dependent
Beffert, U., Cohn, J. S., Petit-Turcotte, C., Tremblay, M., Aumont, N., Ramassamy, C., Davignon, J., & Poirier, J. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01894-6 · Cited by 142 · see citing works
Mutant mice with scrambled brains: understanding the signaling pathways that control cell positioning in the CNSPreprint
Rice, D. S., & Curran, T. (1999) · Genes & Development · doi:10.1101/gad.13.21.2758 · Cited by 142 · see citing works
Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms
Kim, J., Yoon, H., Basak, J., & Kim, J. (2014) · Molecules and Cells · doi:10.14348/molcells.2014.0248 · Cited by 141 · see citing works
“Most studies have demonstrated that apoE3 isoform promotes neurite outgrowth in primary embryonic and adult cortical neurons, as well as neuronal cell lines (Nathan et al., 1994; 2002; Sun et al., 1998).”
Background
Apolipoprotein E &egr;4 and short-term recovery from predominantly mild brain injury
Liberman, J., Stewart, W., Wesnes, K., & Troncoso, J. (2002) · Neurology · doi:10.1212/wnl.58.7.1038 · Cited by 129 · see citing works
Two Distal Downstream Enhancers Direct Expression of the Human Apolipoprotein E Gene to Astrocytes in the Brain
Grehan, S., Tse, E., & Taylor, J. M. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-03-00812.2001 · Cited by 138 · see citing works
α-1-Antichymotrypsin Promotes β-Sheet Amyloid Plaque Deposition in a Transgenic Mouse Model of Alzheimer's Disease
Nilsson, L. N. G., Bales, K. R., DiCarlo, G., Gordon, M. N., Morgan, D., Paul, S. M., & Potter, H. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-05-01444.2001 · Cited by 137 · see citing works
Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-β
Morikawa, M., Fryer, J. D., Sullivan, P. M., Christopher, E., Schindler, S. E., Demattos, R. B., Odell, M., Fagan, A. M., Lashuel, H. A., Walz, T., et al. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.11.005 · Cited by 136 · see citing works
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Risk for Alzheimer's disease correlates with transcriptional activity of the APOE gene
Artiga, M. J., Bullido, M. J., Frank, A., Sastre, I., Recuero, M., Garcia, M. A., Lendon, C. L., Han, S. W., Morris, J. C., Vázquez, J., et al. (1998) · Human Molecular Genetics · doi:10.1093/hmg/7.12.1887 · Cited by 137 · see citing works
APOE, APOE Promoter, and Tau Genotypes and Risk for Concussion in College Athletes
Terrell, T. R., Bostick, R. M., Abramson, R., Xie, D., Barfield, W. R., Cantu, R. C., Stanek, M. K., & Ewing, T. (2008) · Clinical Journal of Sport Medicine · doi:10.1097/jsm.0b013e31815c1d4c · Cited by 129 · see citing works
Impaired neuronal plasticity in transgenic mice expressing human apolipoprotein E4 compared to E3 in a model of entorhinal cortex lesion.
White, F., Nicoll, J. A. R., Roses, A. D., & Horsburgh, K. (2001) · Neurobiology of Disease · doi:10.1006/nbdi.2001.0401 · Cited by 128 · see citing works
Novel Role for Apolipoprotein E in the Central Nervous System
Han, X., Cheng, H., Fryer, J. D., Fagan, A. M., & Holtzman, D. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212340200 · Cited by 126 · see citing works
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Expression Specificity of GFAP Transgenes
Su, M., Hu, H., Lee, Y., D’Azzo, A., Messing, A., & Brenner, M. (2004) · Neurochemical Research · doi:10.1007/s11064-004-6881-1 · Cited by 124 · see citing works
Apolipoprotein E and apolipoprotein E receptors modulate Aβ-induced glial neuroinflammatory responses
LaDu, M. J., Shah, J. A., Reardon, C. A., Getz, G. S., Bu, G., Hu, J., Guo, L., & Van Eldik, L. J. (2001) · Neurochemistry International · doi:10.1016/s0197-0186(01)00050-x · Cited by 118 · see citing works
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Marked regional differences of brain human apolipoprotein e expression in targeted replacement mice
Sullivan, P. M., Mace, B. E., Maeda, N., & Schmechel, D. E. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2003.10.011 · Cited by 113 · see citing works
Apolipoprotein E4 influences amyloid deposition but not cell loss after traumatic brain injury in a mouse model of Alzheimer’s disease
Hartman, R. E., Laurer, H., Longhi, L., Bales, K. R., Paul, S. M., McIntosh, T. K., & Holtzman, D. M. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-23-10083.2002 · Cited by 115 · see citing works
Self-citation
Reduced cerebrovascular reactivity in young adults carrying the APOE ε4 allele
Suri, S., Mackay, C. E., Kelly, M. E., Germuska, M. A., Tunbridge, E. M., Frisoni, G. B., Matthews, P. M., Ebmeier, K. P., Bulte, D. P., & Filippini, N. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2014.05.1755 · Cited by 113 · see citing works
Serum Glial Fibrillary Acidic Protein (GFAP) Is a Marker of Disease Severity in Frontotemporal Lobar Degeneration
Benussi, A., Ashton, N. J., Karikari, T. K., Gazzina, S., Premi, E., Benussi, L., Ghidoni, R., Rodriguez, J. L., Emeršič, A., Binetti, G., et al. (2020) · Journal of Alzheimer’s Disease · doi:10.3233/jad-200608 · Cited by 113 · see citing works
Cerebral Ischemia and Alzheimer's Disease: The Expression of Amyloid-β and Apolipoprotein E in Human Hippocampus
Qi, J., Wu, H., Yang, Y., Wang, D., Chen, Y., Gu, Y., & Liu, T. (2007) · Journal of Alzheimer s Disease · doi:10.3233/jad-2007-12406 · Cited by 107 · see citing works
Apolipoprotein E and Alzheimer disease
Huang, Y. (2006) · Neurology · doi:10.1212/01.wnl.0000192102.41141.9e · Cited by 106 · see citing works
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Untitled work
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Human apoE3 but not apoE4 rescues impaired astrocyte activation in apoE null mice
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O4–01–06: Astrocytes have a reduced capacity to secrete apolipoprotein (APO) E4 leading to substantially reduced brain levels
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Authors: Sun, Y., Wu, S., Bu, G., Onifade, M. K., Patel, S. N., LaDu, M. J., Fagan, A. M., & Holtzman, D. M.
Affiliations: Washington University in St. Louis (US)
University of Chicago (US)
ORCID: Sun, Yuling
Wu, Shan
Bu, Guojun
LaDu, Mary Jo
Fagan, Anne M.
Holtzman, David M.
Venue: The Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 1998-05-01
Volume: 18
Issue: 9
Pages: 3261-3272
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.18-09-03261.1998
PMC: PMC6792658
OpenAlex: W1629602451
Cited by: 213
References: 81
Citations by year: 2026: 1 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 6 · 2021: 6 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 7 · 2016: 2 · 2015: 2 · 2014: 7 · 2013: 1 · 2012: 1
FWCI: 12.91
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-sa
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 184 d)
Locations: Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders: Alzheimer's Association (AG05681, AG13956)
National Institutes of Health (AG05681, AG13956)
National Institute on Aging (R01AG013956, AG 05681, P50AG005681, R37AG013956, AG13956)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords: apolipoprotein E, APOE3, APOE ε4, astrocytes, glial fibrillary acidic protein, neurite outgrowth, hippocampal neurons, low density lipoprotein receptor-related protein, Alzheimer's disease, central nervous system injury, astrocyte-neuron interaction
MeSH terms: Animals, Apolipoproteins E, Astrocytes, Brain, Cells, Cultured, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Humans, Mice, Transgenic, Particle Size, Mice, Apolipoprotein E3, Apolipoprotein E4

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Glial fibrillary acidic protein-apolipoprotein E (apoE) transgenic mice: astrocyte-specific expression and differing biological effects of astrocyte-secreted apoE3 and apoE4 lipoproteins.

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