Hepatic expression of APOE3 Christchurch mitigates APOE4-related Alzheimer’s disease pathologies in mice
Abstract
The ε4 allele of apolipoprotein E (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD) and exacerbates AD-related pathologies. Identifying strategies to mitigate the pathogenic effects of APOE4 remains a critical challenge in the field of AD research. The rare APOE3 Christchurch (APOE3Ch) variant has been suggested to be potentially protective against AD. Our study investigated whether hepatic expression of APOE3Ch could mitigate APOE4-associated AD pathologies. We successfully delivered APOE3Ch or APOE3 into the liver by adeno-associated virus in APP/PS1 mice expressing human APOE4. We observed that hepatic APOE3Ch delivery reduced amyloid-β (Aβ) burden in the brain. Hepatic APOE3Ch expression attenuated neuroinflammation, neurodegeneration, and cognitive impairments. Mechanistically, APOE3Ch expression increased the capacity of Aβ clearance by monocytes and hepatocytes. Our findings demonstrate that hepatic APOE3Ch expression attenuates AD-type pathologies in APOE4-expressing APP/PS1 mice, highlighting liver-directed APOE3Ch gene transfer as a promising therapeutic strategy for APOE4-associated AD.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Cites
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
Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases
Huang, Y., & Mahley, R. W. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.025 · Cited by 829 · see citing works
Arboleda-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
Cheng, Y., Tian, D., & Wang, Y.-J. (2020) · Translational Neurodegeneration · doi:10.1186/s40035-020-00195-1 · Cited by 195 · see citing works
Self-citationMultifaceted 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
Liu, C.-C., Zhao, J., Fu, Y., Inoue, Y., Ren, Y., Chen, Y., Doss, S. V., Shue, F., Jeevaratnam, S., Bastea, L., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01127-0 · Cited by 168 · see citing works
APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1
Tachibana, M., Holm, M.-L., Liu, C.-C., Shinohara, M., Aikawa, T., Oue, H., Yamazaki, Y., Martens, Y. A., Murray, M. E., Sullivan, P. M., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci124853 · Cited by 156 · see citing works
Qosa, H., Abuasal, B. S., Romero, I. A., Weksler, B., Couraud, P.-O., Keller, J. N., & Kaddoumi, A. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.01.023 · Cited by 146 · see citing works
Fitz, N. F., Nam, K. N., Wolfe, C. M., Letronne, F., Playso, B. E., Iordanova, B. E., Kozai, T. D. Y., Biedrzycki, R. J., Kagan, V. E., Tyurina, Y. Y., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23762-0 · Cited by 129 · 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
Self-citationNelson, 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
Physiological β-amyloid clearance by the liver and its therapeutic potential for Alzheimer’s disease
Cheng, Y., He, C.-Y., Tian, D.-Y., Chen, S.-H., Ren, J.-R., Sun, H.-L., Xu, M.-Y., Tan, C.-R., Fan, D.-Y., Jian, J.-M., et al. (2023) · Acta Neuropathologica · doi:10.1007/s00401-023-02559-z · Cited by 105 · see citing works
Self-citationThe role of APOE4 in Alzheimer’s disease: strategies for future therapeutic interventions
Hunsberger, H. C., Pinky, P. D., Smith, W., Suppiramaniam, V., & Reed, M. N. (2019) · Neuronal Signaling · doi:10.1042/ns20180203 · Cited by 94 · see citing works
Wu, Y., Dong, J.-H., Dai, Y.-F., Zhu, M.-Z., Wang, M.-Y., Zhang, Y., Pan, Y.-D., Yuan, X.-R., Guo, Z.-X., Wang, C.-X., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.06.002 · Cited by 84 · see citing works
Self-citationAltered peripheral profile of blood cells in Alzheimer disease
Chen, S., Bu, X., Jin, W., Shen, L., Wang, J., Zhuang, Z.-Q., Zhang, T., Zeng, F., Yao, X., Zhou, H., et al. (2017) · Medicine · doi:10.1097/md.0000000000006843 · Cited by 64 · see citing works
Self-citation<i>APOE3</i> Christchurch Heterozygosity and Autosomal Dominant Alzheimer’s Disease
Quiroz, Y. T., Aguillon, D., Aguirre-Acevedo, D. C., Vasquez, D., Zuluaga, Y., Baena, A. Y., Madrigal, L., Hincapié, L., Sanchez, J. S., Langella, S., et al. (2024) · New England Journal of Medicine · doi:10.1056/nejmoa2308583 · Cited by 63 · see citing works
Yuede, C. M., Lee, H. J., Restivo, J. L., Davis, T. A., Hettinger, J. C., Wallace, C. E., Young, K. L., Hayne, M. R., Bu, G., Li, C.-Z., et al. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20151428 · Cited by 63 · see citing works
Physiological clearance of Aβ by spleen and splenectomy aggravates Alzheimer‐type pathogenesis
Yu, Z., Chen, D., Tan, C., Zeng, G., He, C.-Y., Wang, J., Bu, X., & Wang, Y. (2021) · Aging Cell · doi:10.1111/acel.13533 · Cited by 50 · see citing works
Self-citationLiver exerkine reverses aging- and Alzheimer’s-related memory loss via vasculature
Bieri, G., Pratt, K. J. B., Fuseya, Y., Aghayev, T., Sucharov, J., Horowitz, A. M., Philp, A. R., Fonseca-Valencia, K., Chu, R., Phan, M., et al. (2026) · Cell · doi:10.1016/j.cell.2026.01.024 · Cited by 30 · see citing works
Erythropoietin signaling in peripheral macrophages is required for systemic β‐amyloid clearance
Xu, L., Li, L., Pan, C., Song, J., Zhang, C., Wu, X., Hu, F., Liu, X., Zhang, Z., & Zhang, Z. (2022) · The EMBO Journal · doi:10.15252/embj.2022111038 · Cited by 29 · see citing works
Self-citationTran, K. M., Kwang, N. E., Butler, C. A., Gomez-Arboledas, A., Kawauchi, S., Mar, C., Chao, D., Barahona, R. A., Da Cunha, C., Tsourmas, K. I., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00793-x · Cited by 28 · see citing works
Chen, S., He, C.-Y., Shen, Y., Zeng, G., Tian, D., Cheng, Y., Xu, M., Fan, D., Tan, C., Shi, A., et al. (2021) · Neuroscience Bulletin · doi:10.1007/s12264-021-00779-5 · Cited by 26 · see citing works
Self-citationChen, G., Wang, M., Zhang, Z., Hong, D. K., Ahn, E. H., Liu, X., Kang, S. S., & Ye, K. (2025) · Neuron · doi:10.1016/j.neuron.2024.12.015 · Cited by 21 · see citing works
Self-citationKIBRA regulates amyloid β metabolism by controlling extracellular vesicles secretion
Han, X., Wang, C., Song, L., Wang, X., Tang, S. H., Hou, T., Liu, C., Liang, X., Qiu, C., Wang, Y., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.103980 · Cited by 14 · see citing works
Self-citationYu, Z., Liu, J., Liu, Z., Liu, X., Tuo, J., Li, J., Tu, Y., Tan, Q., Ma, Y., Bai, Y., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14402 · Cited by 10 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Shi, H., Zhao, Y., Wei, Z., Yan-jiang, W., & Bu, X.-L. (2026) · Trends in Neurosciences · doi:10.1016/j.tins.2026.09.009
Self-citation
- Authors
- Tang, J.-Y., Tan, Q., Yu, Z.-Y., Yuan, Z.-Y., Zeng, R., Liu, X.-Y., Zhu, X.-Y., Zhao, Y., Li, J.-H., Bai, Y.-D., Zeng, G.-H., Wang, C., & Wang, Y.-J.
- Affiliations
- Army Medical University (CN)
- Chongqing Medical University (CN)
- Corresponding author
- Wang, Chao
- Wang, Yan-Jiang
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2026-10
- Volume
- 114
- Issue
- 19
- Pages
- 3619-3631.e6
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W7160414360
- Cited by
- 0
- References
- 22
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (82588301, 82271470)
- Chongqing Municipal Science and Technology Bureau
- National Key Research and Development Program of China (2023YFC3605400)
- 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
- APOE ε4, Alzheimer's disease, hepatic gene transfer, adeno-associated virus, amyloid-beta clearance, APP/PS1 mice, neuroinflammation, neurodegeneration, cognitive impairment, monocytes, hepatocytes, liver-directed gene therapy
- MeSH terms
- Alzheimer Disease, Animals, Brain, Humans, Liver, Male, Mice, Transgenic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, Apolipoprotein E3, Apolipoprotein E4
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
