Inhibitory Roles of Apolipoprotein E Christchurch Astrocytes in Curbing Tau Propagation Using Human Pluripotent Stem Cell-Derived Models
Open accessAbstract
Genetic variants in the apolipoprotein E ( APOE ) gene affect the onset and progression of Alzheimer's disease (AD). The APOE Christchurch ( APOE Ch) variant has been identified as the most prominent candidate for preventing the onset and progression of AD. In this study, we generated isogenic APOE3 Ch/ 3 Ch human-induced pluripotent stem cells (iPSCs) from APOE3 / 3 healthy control female iPSCs and induced them into astrocytes. RNA expression analysis revealed the inherent resilience of APOE3 Ch/ 3 Ch astrocytes to induce a reactive state in response to inflammatory cytokines. Moreover, cytokine treatment changed astrocytic morphology with more complexity in APOE3 / 3 astrocytes, but not in APOE3 Ch/ 3 Ch astrocytes, indicating resilience of the rare variant to a reactive state. Interestingly, we observed robust morphological alterations containing more intricate processes when cocultured with iPSC-derived cortical neurons, in which APOE3 Ch/ 3 Ch astrocytes reduced complexity compared with APOE3 / 3 astrocytes. To assess the impacts of tau propagation effects, we next developed a sophisticated and sensitive assay utilizing cortical neurons derived from human iPSCs, previously generated from donors of both sexes. We showed that APOE3 Ch/ 3 Ch astrocytes effectively mitigated tau propagation within iPSC-derived neurons. This study provides important experimental evidence of the characteristic functions exhibited by APOE3Ch/3Ch astrocytes, thereby offering valuable insights for the advancement of novel clinical interventions in AD research.
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Murakami et al. reported no genotype-dependent differences in lipid droplet accumulation or apoE secretion in similarly differentiated iPSC-derived APOE3-Ch astrocytes.
“Our results differ from those of Murakami et al., 37 who used similarly differentiated iPSC‐derived APOE3‐Ch astrocytes but reported no genotype‐dependent differences in lipid droplet accumulation or apoE secretion.”
From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [37]
Cites
Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors
Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007) · Cell · doi:10.1016/j.cell.2007.11.019 · Cited by 20,221 · see citing works
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429 · see citing works
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971 · see citing works
The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, D. J., & Hardy, J. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606210 · Cited by 6,164 · see citing works
2016 Alzheimer's disease facts and figures
Alzheimer's Association (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.03.001 · Cited by 5,069 · see citing works
Propagation of Tau Pathology in a Model of Early Alzheimer's Disease
de Calignon, A., Polydoro, M., Suárez-Calvet, M., William, C., Adamowicz, D. H., Kopeikina, K. J., Pitstick, R., Sahara, N., Ashe, K. H., Carlson, G. A., et al. (2012) · Neuron · doi:10.1016/j.neuron.2011.11.033 · Cited by 1,427 · see citing works
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425 · see citing works
Lin, Y.-T., Seo, J., Gao, F., Feldman, H. M., Wen, H.-L., Penney, J., Cam, H. P., Gjoneska, E., Raja, W. K., Cheng, J., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.05.008 · Cited by 1,125 · see citing works
Trans-Synaptic Spread of Tau Pathology In Vivo
Liu, L., Drouet, V., Wu, J., Witter, M. P., Small, S. A., Clelland, C. L. T., & Duff, K. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031302 · Cited by 994 · see citing works
Neuronal activity enhances tau propagation and tau pathology in vivo
Wu, J. W., Hussaini, S. A., Bastille, I. M., Rodriguez, G. A., Mrejeru, A., Rilett, K., Sanders, D. W., Cook, C., Fu, H., Boonen, R. A. C. M., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4328 · Cited by 820 · see citing works
Wilhelmsson, U., Bushong, E. A., Price, D. L., Smarr, B. L., Phung, V., Terada, M., Ellisman, M. H., & Pekny, M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602841103 · Cited by 643 · see citing works
Physiological release of endogenous tau is stimulated by neuronal activity
Pooler, A. M., Phillips, E. C., Lau, D. H. W., Noble, W., & Hanger, D. P. (2013) · The EMBO Reports · doi:10.1038/embor.2013.15 · Cited by 642 · see citing works
Modeling familial Alzheimer's disease with induced pluripotent stem cells
Yagi, T., Ito, D., Okada, Y., Akamatsu, W., Nihei, Y., Yoshizaki, T., Yamanaka, S., Okano, H., & Suzuki, N. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr394 · Cited by 599 · see citing works
Self-citationArboleda-Velasquez, J. F., Lopera, F., O’Hare, M., Delgado-Tirado, S., Marino, C., Chmielewska, N., Saez-Torres, K. L., Amarnani, D., Schultz, A. P., Sperling, R. A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0611-3 · Cited by 598 · see citing works
Neuroinflammatory astrocyte subtypes in the mouse brain
Hasel, P., Rose, I. V. L., Sadick, J. S., Kim, R. D., & Liddelow, S. A. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00905-6 · Cited by 586 · see citing works
Neuronal activity regulates extracellular tau in vivo
Yamada, K., Holth, J. K., Liao, F., Stewart, F. R., Mahan, T. E., Jiang, H., Cirrito, J. R., Patel, T. K., Hochgräfe, K., Mandelkow, E., et al. (2014) · The Journal of Experimental Medicine · doi:10.1084/jem.20131685 · Cited by 574 · see citing works
LRP1 is a master regulator of tau uptake and spread
Rauch, J. N., Luna, G., Guzman, E., Audouard, M., Challis, C., Sibih, Y. E., Leshuk, C., Hernandez, I., Wegmann, S., Hyman, B. T., et al. (2020) · Nature · doi:10.1038/s41586-020-2156-5 · Cited by 541 · see citing works
Cholesterol and matrisome pathways dysregulated in astrocytes and microglia
TCW, J., Qian, L., Pipalia, N. H., Chao, M. J., Liang, S. A., Shi, Y., Jain, B. R., Bertelsen, S. E., Kapoor, M., Marcora, E., et al. (2022) · Cell · doi:10.1016/j.cell.2022.05.017 · Cited by 411 · see citing works
Self-citation<i>APOE4</i> disrupts intracellular lipid homeostasis in human iPSC-derived glia
Sienski, G., Narayan, P., Bonner, J. M., Kory, N., Boland, S., Arczewska, A. A., Ralvenius, W. T., Akay, L., Lockshin, E., He, L., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.aaz4564 · Cited by 336 · see citing works
Chun, H., Im, H., Kang, Y. J., Kim, Y., Shin, J. H., Won, W., Lim, J., Ju, Y. H., Park, Y. M., Kim, S., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-00735-y · Cited by 274 · see citing works
Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice
Caballero, B., Bourdenx, M., Luengo, E., Diaz, A., Sohn, P. D., Chen, X., Wang, C., Juste, Y. R., Wegmann, S., Patel, B., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22501-9 · Cited by 223 · see citing works
Self-citationPrevention of tau seeding and propagation by immunotherapy with a central tau epitope antibody
Albert, M., Mairet‐Coello, G., Danis, C., Lieger, S., Caillierez, R., Carrier, S., Skrobala, E., Landrieu, I., Michel, A., Schmitt, M., et al. (2019) · Brain · doi:10.1093/brain/awz100 · Cited by 177 · see citing works
Wardell, M. R., Brennan, S. O., Janus, E. D., Fraser, R., & Carrell, R. W. (1987) · Journal of Clinical Investigation · doi:10.1172/jci113096 · Cited by 159 · see citing works
Experimental evidence for the age dependence of tau protein spread in the brain
Wegmann, S., Bennett, R. E., Delorme, L., Robbins, A. B., Hu, M., MacKenzie, D., Kirk, M. J., Schiantarelli, J., Tunio, N., Amaral, A. C., et al. (2019) · Science Advances · doi:10.1126/sciadv.aaw6404 · Cited by 144 · see citing works
APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread
Chen, Y., Song, S., Parhizkar, S., Lord, J., Zhu, Y., Strickland, M. R., Wang, C., Park, J., Tabor, G. T., Jiang, H., et al. (2024) · Cell · doi:10.1016/j.cell.2023.11.029 · Cited by 120 · see citing works
Nelson, M. R., Liu, P., Agrawal, A., Yip, O., Blumenfeld, J., Traglia, M., Kim, M. J., Koutsodendris, N., Rao, A., Grone, B., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01480-8 · Cited by 118 · see citing works
Familial Alzheimer’s disease mutations in PSEN1 lead to premature human stem cell neurogenesis
Arber, C., Lovejoy, C., Harris, L., Willumsen, N., Alatza, A., Casey, J. M., Lines, G., Kerins, C., Mueller, A. K., Zetterberg, H., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108615 · Cited by 116 · see citing works
<i>APOE2</i> eases cognitive decline during Aging: Clinical and preclinical evaluations
Shinohara, M., Kanekiyo, T., Yang, L., Linthicum, D., Shinohara, M., Fu, Y., Price, L., Frisch‐Daiello, J. L., Han, X., Fryer, J. D., et al. (2016) · Annals of Neurology · doi:10.1002/ana.24628 · Cited by 111 · see citing works
<i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia
Liu, C.-C., Murray, M. E., Li, X., Zhao, N., Wang, N., Heckman, M. G., Shue, F., Martens, Y., Li, Y., Raulin, A.-C., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abc9375 · Cited by 108 · see citing works
de Leeuw, S. M., Kirschner, A. W. T., Lindner, K., Rust, R., Budny, V., Wolski, W. E., Gavin, A.-C., Nitsch, R. M., & Tackenberg, C. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.11.007 · Cited by 105 · see citing works
Association of Rare <i>APOE</i> Missense Variants V236E and R251G With Risk of Alzheimer Disease
Le Guen, Y., Belloy, M. E., Grenier-Boley, B., de Rojas, I., Castillo-Morales, A., Jansen, I., Nicolas, A., Bellenguez, C., Dalmasso, C., Küçükali, F., et al. (2022) · JAMA Neurology · doi:10.1001/jamaneurol.2022.1166 · Cited by 93 · see citing works
Sepulveda-Falla, D., Sanchez, J. S., Almeida, M. C., Boassa, D., Acosta-Uribe, J., Vila-Castelar, C., Ramirez-Gomez, L., Baena, A., Aguillon, D., Villalba-Moreno, N. D., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02467-8 · Cited by 92 · see citing works
APOE2 is associated with longevity independent of Alzheimer’s disease
Shinohara, M., Kanekiyo, T., Tachibana, M., Kurti, A., Shinohara, M., Fu, Y., Zhao, J., Han, X., Sullivan, P. M., Rebeck, G. W., et al. (2020) · eLife · doi:10.7554/elife.62199 · Cited by 82 · see citing works
Human Astrocytes Model Derived from Induced Pluripotent Stem Cells
Leventoux, N., Morimoto, S., Imaizumi, K., Sato, Y., Takahashi, S., Mashima, K., Ishikawa, M., Sonn, I., Kondo, T., Watanabe, H., et al. (2020) · Cells · doi:10.3390/cells9122680 · Cited by 60 · see citing works
Self-citationTakeda, S. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01274 · Cited by 51 · see citing works
Pocovi, M., Cenarro, A., Civeir, F., Myers, R. H., Casao, E., Esteban, M., & Ordovas, J. M. (1996) · Atherosclerosis · doi:10.1016/0021-9150(95)06745-0 · Cited by 42 · see citing works
Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network
the Dominantly Inherited Alzheimer Network (DIAN), Karch, C. M. M., Hernández, D., Wang, J., Marsh, J. A., Hewitt, A. W., Hsu, S., Norton, J. B., Levitch, D., Donahue, T. A., et al. (2018) · Alzheimer s Research & Therapy · doi:10.1186/s13195-018-0400-0 · Cited by 37 · see citing works
Self-citationImplication of tau propagation on neurodegeneration in Alzheimer’s disease
Lamontagne-Kam, D., Ulfat, A. K., Hervé, V., Vu, T.-M., & Brouillette, J. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1219299 · Cited by 25 · see citing works
Watanabe, H., Murakami, R., Tsumagari, K., Morimoto, S., Hashimoto, T., Imaizumi, K., Sonn, I., Yamada, K., Saito, Y., Murayama, S., et al. (2023) · Stem Cell Reports · doi:10.1016/j.stemcr.2023.08.002 · Cited by 24 · see citing works
Self-citationImpact of APOE genotype on prion-type propagation of tauopathy
Williams, T., Ruiz, A. J., Ruiz, A. M., Vo, Q., Tsering, W., Xu, G. M., McFarland, K. N., Giasson, B. I., Sullivan, P. M., Borchelt, D., et al. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01359-y · Cited by 21 · see citing works
Generation of region-specific and high-purity neurons from human feeder-free iPSCs
Sato, T., Imaizumi, K., Watanabe, H., Ishikawa, M., & Okano, H. (2021) · Neuroscience Letters · doi:10.1016/j.neulet.2021.135676 · Cited by 20 · see citing works
Self-citationRolleri, M., Vivona, N., Emmanuele, G., Cefalu, A. B., Pisciotta, L., Guido, V., Noto, D., Fiore, B., Barbagallo, C. M., Notarbartolo, A., et al. (2003) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/s0939-4753(03)80024-8 · Cited by 16 · see citing works
Watanabe, H., Imaizumi, K., Cai, T., Zhou, Z., Tomita, T., & Okano, H. (2021) · eNeuro · doi:10.1523/eneuro.0500-20.2021 · Cited by 14 · see citing works
Self-citationTau propagation is dependent on the genetic background of mouse strains
Dujardin, S., Fernandes, A., Bannon, R., Commins, C., De Los Santos, M., Kamath, T. V., Hayashi, M., & Hyman, B. T. (2022) · Brain Communications · doi:10.1093/braincomms/fcac048 · Cited by 11 · see citing works
Henao‐Restrepo, J., López‐Murillo, C., Valderrama‐Carmona, P., Orozco‐Santa, N., Gomez, J., Gutiérrez‐Vargas, J., Moraga, R., Toledo, J., Littau, J. L., Härtel, S., et al. (2023) · Brain Pathology · doi:10.1111/bpa.13119 · Cited by 11 · see citing works
Apolipoprotein E isoform does not influence trans-synaptic spread of tau pathology in a mouse model
Davies, C., Tulloch, J., Yip, E., Currie, L., Colom‐Cadena, M., Wegmann, S., Hyman, B. T., Wilkins, L., Hooley, M., Tzioras, M., et al. (2023) · Brain and Neuroscience Advances · doi:10.1177/23982128231191046 · Cited by 11 · see citing works
Spreading of Tau Protein Does Not Depend on Aggregation Propensity
Rodrigues, S., Anglada‐Huguet, M., Hochgräfe, K., Kaniyappan, S., Wegmann, S., & Mandelkow, E. (2023) · Journal of Molecular Neuroscience · doi:10.1007/s12031-023-02143-w · Cited by 11 · see citing works
Mazzarino, R. C., Perez-Corredor, P. A., Vanderleest, T. E., Vacano, G. N., Sanchez, J. S., Villalba‐Moreno, N. D., Krausemann, S., Mendivil-Perez, M., Aguillon, D. F., Jiménez-Del-Río, M., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.01.11.523290 · Cited by 7 · see citing works
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- Authors
- Murakami, R., Watanabe, H., Hashimoto, H., Kashiwagi-Hakozaki, M., Hashimoto, T., Karch, C. M., the Dominantly Inherited Alzheimer Network (DIAN), Iwatsubo, T., & Okano, H.
- Affiliations
- Keio University (JP)
- National Center of Neurology and Psychiatry (JP)
- Washington University in St. Louis (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2024-04-22
- Volume
- 44
- Issue
- 24
- Pages
- e1709232024
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC11170944
- OpenAlex
- W4394994802
- Cited by
- 9
- References
- 49
- Citations by year
- 2026: 3 · 2025: 6
- FWCI
- 2.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- Japan Agency for Medical Research and Development (JP17pc0101006)
- MEXT | Japan Society for the Promotion of Science (JP21H05633, 22J11065)
- HHS | NIH | National Institute on Aging (U19AG032438)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- apolipoprotein E, APOE3, astrocytes, tau propagation, Alzheimer's disease, human induced pluripotent stem cells, iPSC-derived neurons, astrocyte-neuron co-culture, astrocyte activation, inflammatory cytokines, astrocyte morphology, sex differences
- MeSH terms
- Alzheimer Disease, Apolipoproteins E, Astrocytes, Cells, Cultured, Female, Humans, Neurons, tau Proteins, Coculture Techniques, Apolipoprotein E3, Induced Pluripotent Stem Cells
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