APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread
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A recent case report described an individual who was a homozygous carrier of the APOE3 Christchurch (APOE3ch) mutation and resistant to autosomal dominant Alzheimer's Disease (AD) caused by a PSEN1-E280A mutation. Whether APOE3ch contributed to the protective effect remains unclear. We generated a humanized APOE3ch knock-in mouse and crossed it to an amyloid-β (Aβ) plaque-depositing model. We injected AD-tau brain extract to investigate tau seeding and spreading in the presence or absence of amyloid. Similar to the case report, APOE3ch expression resulted in peripheral dyslipidemia and a marked reduction in plaque-associated tau pathology. Additionally, we observed decreased amyloid response and enhanced microglial response around plaques. We also demonstrate increased myeloid cell phagocytosis and degradation of tau aggregates linked to weaker APOE3ch binding to heparin sulfate proteoglycans. APOE3ch influences the microglial response to Aβ plaques, which suppresses Aβ-induced tau seeding and spreading. The results reveal new possibilities to target Aβ-induced tauopathy.
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The homozygous Christchurch mutation suppresses AD pathologies in amyloid and non-amyloid mouse models.
“The homozygous Christchurch mutation also suppresses AD pathologies in amyloid and non-amyloid mouse models26,27.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [26]
Similar to ApoE2, Christchurch (R136S) mutation is protective in autosomal dominant AD cases and AD mouse models.
“Similar to ApoE2, Christchurch (R136S) mutation is protective in autosomal dominant AD cases24,25 and AD mouse models26,27.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [26]
Decreased LDLR binding may contribute to the protective effects of the R136S mutation.
“Decreased LDLR binding may thus also contribute to the protective effects of this mutation26,27.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [26]
ApoeCh mice exhibited elevated plasma cholesterol (CHOL), mainly contributed by males.
“ApoeCh mice exhibited elevated plasma cholesterol (CHOL), mainly contributed by males (Fig. 1b) [15, 41].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [41]
While this report was being prepared, independent studies reported similar findings.
“While this report was being prepared, independent studies reported similar findings [41, 76, 77].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [41]
The impact of the Christchurch variant on microglial activation appears to be dependent on the stimulus, i.e., plaques or tau-laden neurons.
“Thus, the impact of the Christchurch variant appears to be dependent on the stimulus – i.e., plaques or tau-laden neurons.”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [41]
The reduction in plaque load and glial presence and amelioration of damage by ApoeCh in 5xFAD is consistent with the study involving humanized APOE3Ch knock-in mice crossed to APP/PS1 mice.
“consistent with the study involving humanized APOE3Ch knock-in mice crossed to APP/PS1 mice [41].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [41]
In mice homozygous for the Christchurch variant, microglial activation states are suppressed in PS19 mice (tau-associated pathology), promoting a homeostatic or "disease protective" response, whereas they are enhanced in APP/PS1 mice (amyloid-associated pathology), promoting a "disease-associated" state.
“In mice homozygous for the Christchurch variant, these studies indicate that microglial activation states are suppressed in PS19 mice (tau-associated pathology), promoting a homeostatic or “disease protective” response, whereas they are enhanced in APP/PS1 mice (amyloid-associated pathology), promoting a “disease-associated” state.”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [41]
HSPGs are responsible for neuronal uptake of tau and the R136S mutation causes impaired binding affinity of APOE to HSPGs, leading to reduced tau pathology.
“HSPGs are responsible for neuronal uptake of tau and the R136S mutation causes impaired binding affinity of APOE to HSPGs, leading to reduced tau pathology [15, 41, 76, 84, 85].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [41]
Previous studies provide evidence that the Christchurch variant reduces AD pathology and associated CNS damage at least in part through alterations in receptor binding to LRP1, LDLR and/or HSPGs.
“Previous studies provide evidence that the Christchurch variant reduces AD pathology and associated CNS damage at least in part through alterations in receptor binding to LRP1, LDLR and/or HSPGs [15, 41, 76].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [41]
Chen et al. report no difference in tau with introduction of humanized APOE3Ch in the absence of amyloidosis.
“Chen et al. [41] report no difference in tau with introduction of humanized APOE3Ch in the absence of amyloidosis.”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [41]
E3S/S protected against toxicity induced by inoculation of AD-tau in a transgenic amyloid mouse model.
“Additionally, E3S/S also protected against toxicity induced by inoculation of AD-tau in a transgenic amyloid mouse model15.”
From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [15]
Previous studies elucidated robust protective effects of R136S in an E3 amyloid model induced by tau aggregates isolated from AD brains (AD-tau).
“Previous studies elucidated robust protective effects of R136S in an E3 amyloid model induced by tau aggregates isolated from AD brains (AD-tau)15.”
From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [15]
Unlike Chen et al, we observed similar APOE expression in E3 and E3S/S mice in male plasma.
“Unlike Chen et al15, which reported elevated plasma APOE expression in male E3S/S mice, we observed similar APOE expression in E3 and E3S/S mice in male plasma.”
From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [15]
E3S/S microglia show increased tau uptake and clearance.
“These findings suggest that E3S/S microglia show increased tau uptake and clearance, consistent with prior studies15,42.”
From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [15]
Previous findings showed that R136S mutation enhances microglial response around amyloid plaques on E3 background, but downregulates disease-associated gene profiles on E4 background.
“Previous findings showed that R136S mutation enhances microglial response around amyloid plaques on E3 background15, but downregulates disease-associated gene profiles on E4 background14.”
From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [15]
APOE3ch's effects on tau-related phenotypes become most apparent in the context of elevated Aβ levels.
“This is consistent with other studies showing that APOE3ch’s effects on tau-related phenotypes become most apparent in the context of elevated Aβ levels (Chen et al., 2024).”
From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Chen et al., 2024
This prediction was confirmed in vivo in 2023 by two studies that used mouse models expressing human APOE3 or APOE4 with the Christchurch mutation, which showed amelioration of AD phenotypes when compared with APOE3 or APOE4 mice, particularly those related to tau accumulation and microglial response.
“This prediction was confirmed in vivo in 2023 by two studies that used mouse models expressing human APOE3 or APOE4 with the Christchurch mutation, which showed amelioration of AD phenotypes when compared with APOE3 or APOE4 mice, particularly those related to tau accumulation and microglial response197,198.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [198]
APOE3Ch expression leads to reduced levels of NFTs and Aβ plaques in an amyloid model crossed with APOE3Ch knockin mice inoculated with human tau.
“For instance, APOE3Ch expression leads to reduced levels of NFTs and Aβ plaques in an amyloid model crossed with APOE3Ch knockin mice inoculated with human tau (Chen et al., 2024).”
From APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells (2026) · cites this paper as Chen et al., 2024
APOE3Ch reduces binding to heparan sulfate proteoglycans, promoting cellular uptake and tau degradation and reducing tauopathy propagation.
“Mechanistic studies demonstrate that the APOE3Ch variant reduces binding to heparan sulfate proteoglycans (HSPGs), promoting cellular uptake and tau degradation and reducing tauopathy propagation. 5 , 6”
Knock-in expression of APOE3Ch in APP/PS1 amyloid model mice resulted in a significant decrease in Aβ-driven tau seeding and spreading.
“Knock-in expression of APOE3Ch in APP/PS1 amyloid model mice resulted in a modest reduction of amyloid pathology, a significant decrease in Aβ-driven tau seeding and spreading, and dampened microglial activation [4].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [4]
Knock-in expression of APOE3Ch in APP/PS1 amyloid model mice resulted in dampened microglial activation.
“Knock-in expression of APOE3Ch in APP/PS1 amyloid model mice resulted in a modest reduction of amyloid pathology, a significant decrease in Aβ-driven tau seeding and spreading, and dampened microglial activation [4].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [4]
Knock-in expression of APOE3Ch in APP/PS1 amyloid model mice resulted in a modest reduction of amyloid pathology.
“Knock-in expression of APOE3Ch in APP/PS1 amyloid model mice resulted in a modest reduction of amyloid pathology, a significant decrease in Aβ-driven tau seeding and spreading, and dampened microglial activation [4].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [4]
Astrocytic APOE3Ch expression reduces amyloid plaques in the 5xFAD mouse model.
“we also found that astrocytic APOE3Ch expression reduces amyloid plaques in the 5xFAD mouse model.”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [4]
Mounting evidence from human-based, in vitro, and in vivo studies has linked APOE3Ch to reduction in tau pathology.
“Mounting evidence from human-based, in vitro, and in vivo studies has linked APOE3Ch to reduction in tau pathology [3–7, 24, 26, 41, 42].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [4]
Multiple studies have demonstrated that APOECh mutation broadly suppresses gliosis, dampens inflammatory gene expression, and modulates DAM phenotypes in an amyloid and tau-context dependent manner.
“Multiple studies have demonstrated that APOECh mutation broadly suppresses gliosis, dampens inflammatory gene expression, and modulates disease-associated microglial (DAM) phenotypes in an amyloid and tau-context dependent manner [4, 5, 7, 42, 50].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [4]
Reports have shown increased microglial engagement to plaques.
“This observation is in contradiction with reports of increased microglial engagement to plaques [4, 7].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [4]
APOE3Ch knockin led to overall decrease in both astrocytosis and microglial activation and increased CD68-positive microglial clustering compared with APOE3 knockin in APP/PS1 mice.
“APOE3Ch knockin led to overall decrease in both astrocytosis and microglial activation and, in parallel, increased CD68-positive microglial clustering compared with APOE3 knockin in APP/PS1 mice [4].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [4]
APOE3-Ch has been associated with reduced Alzheimer's disease risk and neuroprotection in individuals carrying high-risk genetic mutations for AD.
“APOE3‐Ch has been associated with reduced Alzheimer's disease (AD) risk and neuroprotection in individuals carrying high‐risk genetic mutations for AD.”
From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [8]
APOE3-Ch mice have exhibited peripheral dyslipidemia, including elevated APOE and APOB levels, as well as increased association of APOE with VLDL and low-density lipoproteins LDL.
“APOE3‐Ch mice have exhibited peripheral dyslipidemia, including elevated APOE and APOB levels, as well as increased association of APOE with VLDL and low‐density lipoproteins LDL. 8”
From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [8]
Chen et al. demonstrated that APOE3-Ch myeloid cells have significantly enhanced uptake of tau fibrils-mediated by both HSPGs and LRP1-along with increased degradation and reduced tau release after phagocytosis, suggesting a cell-autonomous protective role for APOE3-Ch in limiting tau spread.
“Notably, their analysis of APOE3‐Ch myeloid cells demonstrated significantly enhanced uptake of tau fibrils—mediated by both HSPGs and LRP1—along with increased degradation and reduced tau release after phagocytosis, suggesting a cell‐autonomous, protective role for APOE3‐Ch in limiting tau spread.”
From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [8]
Unlike Chen et al, we observed similar APOE levels in E3 and E3S/S mice in male plasma.
“However, unlike Chen et al15, which reported elevated plasma APOE levels in male E3S/S mice, we observed similar APOE levels in E3 and E3S/S mice in male plasma.”
From <i>APOE3</i> - <i>R136S</i> mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [15]
The R136S mutation enhances microglial response around amyloid plaques on E3 background.
“Previous findings showed that R136S mutation enhances microglial response around amyloid plaques on E3 background15”
From <i>APOE3</i> - <i>R136S</i> mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [15]
E3S/S protected against toxicity induced by inoculation of AD-tau in a transgenic amyloid mouse model.
“Additionally, E3S/S also protected against toxicity induced by inoculation of AD-tau in a transgenic amyloid mouse model15.”
From <i>APOE3</i> - <i>R136S</i> mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [15]
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Behavioral Consequences of NMDA Antagonist-Induced Neuroapoptosis in the Infant Mouse Brain
Yuede, C. M., Wozniak, D. F., Creeley, C. E., Taylor, G. T., Olney, J. W., & Farber, N. B. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011374 · Cited by 29 · see citing works
Self-citationMotivational Disturbances and Effects of L-dopa Administration in Neurofibromatosis-1 Model Mice
Wozniak, D. F., Diggs‐Andrews, K. A., Conyers, S. B., Yuede, C. M., Dearborn, J. T., Brown, J. A., Tokuda, K., Izumi, Y., Zorumski, C. F., & Gutmann, D. H. (2013) · PLoS ONE · doi:10.1371/journal.pone.0066024 · Cited by 27 · see citing works
Self-citationApolipoprotein E Recognizes Alzheimer's Disease Associated 3‐O Sulfation of Heparan Sulfate
Mah, D., Zhu, Y., Su, G., Zhao, J., Canning, A., Gibson, J. M., Song, X., Stancanelli, E., Xu, Y., Zhang, F., et al. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202212636 · Cited by 23 · see citing works
Self-citationOndrejčák, T., Klyubin, I. V., Hu, N., O’Malley, T. T., Corbett, G. T., Winters, R., Perkinton, M. S., Billinton, A., Prenderville, J. A., Walsh, D. M., et al. (2023) · Journal of Neuroscience · doi:10.1523/jneurosci.0082-23.2023 · Cited by 17 · see citing works
Correction: In Vivo Human Apolipoprotein E Isoform Fractional Turnover Rates in the CNS
Wildsmith, K. R., Basak, J. M., Patterson, B. W., Pyatkivskyy, Y., Kim, J., Yarasheski, K. E., Wang, J. X., Mawuenyega, K. G., Jiang, H., Parsadanian, M., et al. (2012) · PLoS ONE · doi:10.1371/annotation/9bd329b7-cdea-45ec-a4aa-a173855dc0b9 · Cited by 4 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
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
Guo, J. L., Braun, D., Fitzgerald, G. A., Hsieh, Y.-T., Rougé, L., Litvinchuk, A., Steffek, M., Propson, N. E., Heffner, C. M., Discenza, C., et al. (2025) · Cell · doi:10.1016/j.cell.2024.10.027 · Cited by 91 · see citing works
“26,27 Studies suggest that poorly lipidated ApoE may seed A b due to its propensity to aggregate and that lipidated ApoE is protective in AD models.”
Self-citationVance, J. M., Farrer, L. A., Huang, Y., Cruchaga, C., Hyman, B. T., Pericak‐Vance, M. A., Goate, A. M., Greicius, M. D., Griswold, A. J., Haines, J. L., et al. (2024) · Annals of Neurology · doi:10.1002/ana.26864 · Cited by 52 · see citing works
Self-citationSun, G. G., Wang, C., Mazzarino, R. C., Perez-Corredor, P. A., Davtyan, H., Blurton-Jones, M., Lopera, F., Arboleda-Velasquez, J. F., & Shi, Y. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114982 · Cited by 36 · see citing works
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Preman, P., Moechars, D., Fertan, E., Wolfs, L., Serneels, L., Shah, D., Lamote, J., Poovathingal, S., Snellinx, A., Mancuso, R., et al. (2024) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00162-7 · Cited by 32 · see citing works
Tran, 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
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Current insights into apolipoprotein E and the immune response in Alzheimer's disease
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Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes
Tian, X., Rivera, E. K., Hwang, I., Nikitina, A. A., Smith, J. A., Cho, Y. J., Sala‐Jarque, J., DuBose, A., Andriola, C., Gollan‐Myers, T., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70589 · Cited by 7 · see citing works
Miyashita, A., Obinata, A., Hara, N., Mitsumori, R., Kaneda, D., Hashizume, Y., Sano, T., Takao, M., Gabdulkhaev, R., Tada, M., et al. (2025) · Journal of Alzheimer’s Disease · doi:10.1177/13872877251340710 · Cited by 5 · see citing works
Pineda‐Lopez, L., Aguillon, D., Villar‐Vesga, J., Valderrama‐Carmona, P., Guerrero, A., Upreti, A., Arevalo‐Alquichire, S., Correa, L., Mendez‐Castellanos, K., Castaño, D., et al. (2026) · Alzheimer's & Dementia · doi:10.1002/alz.71148 · Cited by 4 · see citing works
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Self-citationFrisch, C., Baker, L., Srinivasan, G., Mintah, A. E., Leyasi, S., Pedroza, M., Galyon, B., & Brafman, D. A. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1856154
Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice
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Rodriguez Martinez, P. J., Yslas, A. R., Inoue, Y., Parsons, T. M., Baker, S. K., Lu, W., Raulin, A.-C., & Kanekiyo, T. (2026) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2026.1778856
- Authors
- Chen, Y., Song, S., Parhizkar, S., Lord, J., Zhu, Y., Strickland, M. R., Wang, C., Park, J., Tabor, G. T., Jiang, H., Li, K., Davis, A. A., Yuede, C. M., Colonna, M., Ulrich, J. D., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Holtzman, David M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2024-01
- Volume
- 187
- Issue
- 2
- Pages
- 428-445.e20
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC10842861
- OpenAlex
- W4389555283
- Semantic Scholar
- dd0a161e6b4dc0b8553719d5106f7b4cb15b4dbf
- Cited by
- 120
- References
- 49
- Citations by year
- 2026: 38 · 2025: 46 · 2024: 36
- FWCI
- 21.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 383 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Alzheimer's Association (AARF-21-850865)
- JPB Foundation
- Cure Alzheimer's Fund
- National Institutes of Health (RF1AG047644, RF1NS090934)
- 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
- Alzheimer's disease, tau seeding, tauopathy, amyloid plaques, microglial activation, heparan sulfate proteoglycans
- MeSH terms
- Case Reports as Topic, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Humans, Mice, Transgenic, Amyloid beta-Peptides, tau Proteins, Microglia, Mice, Apolipoprotein E3, Plaque, Amyloid, Amyloidogenic Proteins
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.
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