Species: Mouse
Genes: APOE
Mutations: APOE R154S (Christchurch)
Modification: APOE: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL/6J
Availability: Direct inquiries to David Holtzman.

Summary

In these knock-in mice, the coding region of the mouse Apoe gene was replaced with the human APOE3 sequence containing the Christchurch mutation. Expression of the humanized gene is under the control of endogenous mouse regulatory elements.

To study the effect of the Christchurch mutation, mice homozygous for the APOE3-Christchurch allele (APOE3Ch) were compared with knock-in mice homozygous for the wild-type human APOE3 allele (APOE3). The initial characterization of the APOE3Ch mice included animals of both sexes, studied at 3 or 10 months old (Chen et al., 2024).

Peripheral phenotypes

The Christchurch mutation has been associated with lipid dyshomeostasis in humans, as discussed here. APOE3Ch mice also show signs of dyslipidemia: Levels of plasma ApoE protein and plasma cholesterol were elevated in APOE3Ch mice, compared with APOE3 mice, and ApoE was associated with high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very low-density lipoprotein (vLDL) particles in the plasma of APOE3Ch mice but only with HDL particles in APOE3 mice.

Over time, APOE3Ch mice gained more weight than APOE3 mice, with genotype-dependent differences in body weight apparent by 3 months of age in males and by 10 months in females.

CNS lipid metabolism

Levels of total cholesterol in the cerebrospinal fluid were similar in APOE3 and APOE3Ch mice at both 3 and 10 months of age.

The levels of ApoE in the CSF and in brain lysates were similar between genotypes at 3 months, but were elevated in male APOE3Ch mice, compared with APOE3 males, at 10 months.

Levels of the lipid transporter ABCA1 (ATP-binding cassette transporter A1), the APOE receptors LDLR (low-density lipoprotein receptor) and LRP1 (low-density lipoprotein receptor-related protein 1), and the lipid-pathway regulator ACSL1 (Acyl-CoA synthetase long-chain family member 1) in brain lysates did not differ between genotypes at 3 or 10 months. However, sex differences were seen among APOE3Ch mice at 10 months, with lower levels of ABCA1, LDLR, and LRP1 in females than males.

Glial phenotypes

The initial characterization of APOE3Ch mice did not include a detailed description of glial cells. However, the volumes occupied by the astroglial marker GFAP and the microglial marker Iba1 in the hippocampi and cortices of 10-month-old mice did not differ between APOE3Ch and APOE3 mice.

Behavioral phenotypes

Performance in the Y maze and fear conditioning tests did not differ between genotypes in mice tested between 8 and 10 months of age.

Applications of the model

The effect of the Christchurch mutation on the responses of myeloid cells to fibrillar Aβ or tau has been studied using bone marrow-derived macrophages (BMDMs) from APOE3Ch and APOE3 mice. Under basal conditions, APOE3Ch and APOE3 BMDMs did not differ in their uptake of Aβ fibrils. However, pretreatment with tau fibrils enhanced the uptake of Aβ by APOE3Ch BMDMs, while having no effect on Aβ uptake by APOE3 BMDMs. Conversely, the Christchurch mutation increased phagocytosis of tau fibrils by BMDMs, the internalized tau fibrils were degraded more quickly in APOE3Ch BMDMs than APOE3 BMDMs, and less of the internalized tau was released by cells carrying the Christchurch mutation. Pretreatment with Aβ enhanced tau uptake by cells of both genotypes.

These in vitro results partially reflected findings in vivo. As noted above, the Christchurch mutation did not affect the uptake of Aβ fibrils in vitro in the absence of tau fibrils. In vivo, the Christchurch mutation had only a minor effect on fibrillar plaque burden, as observed when comparing APOE3Ch or APOE3 mice crossed with APPPS1 mice. While the Christchurch mutation affected the uptake, degradation, and release of tau fibrils in vitro, the mutation had little noticeable effect on the propagation of tau pathology in mice who had received intracerebral injections of tau fibrils (APOE3Ch compared with APOE3). In the presence of both amyloid and tau fibrils, the Christchurch mutation attenuated amyloid pathology and partially suppressed tau seeding and spreading (see APOE3Ch knock-in, floxed (CureAlz) x APPPS1, tau intracerebral injection).

Modification details

CRISPR was used to introduce the Christchurch mutation into the APOE gene of APOE3 Knock-In, floxed (CureAlz) mice. In these mice, the coding region of the mouse Apoe gene—from the translation initiation codon in exon 2 to the termination codon in exon 4—is replaced by the corresponding human APOE (ε3 allele) sequence, flanked by loxP sites. Expression of the humanized gene is under the control of endogenous mouse regulatory elements.

Related Models

APOE3Ch (Cornell). APOE3Ch (Cornell) mice express human APOE3 with the Christchurch mutation, under the control of mouse regulatory elements (Naguib et al., 2025). Levels of microglial, astrocytic, oligodendroglial, and synaptic markers and network activity were comparable in APOE3Ch (Cornell) mice and knock-in mice expressing wild-type human APOE3.

APOE3Ch (Cornell) x PS19. To study the effects of the Christchurch mutation on tau pathology, APOE3 knock-in mice with or without the Christchurch mutation were intercrossed with PS19 mice, which carry a human MAPT transgene with the P301S mutation linked to frontotemporal dementia (Naguib et al., 2025). The crosses generated mice homozygous for the humanized APOE alleles and hemizygous for the MAPT-P301S transgene. The Christchurch mutation decreased tau pathology and blunted tau-induced losses of synaptic and myelin markers, alterations in network activity, and microglial interferon responses.

APOE3Ch knock-in, floxed (CureAlz), tau intracerebral injection. To study the effects of the Christchurch mutation on tau seeding and spreading, tau fibrils from an AD brain were injected into the brains of APOE3Ch mice or knock-in mice homozygous for the wild-type human APOE3 allele. The Christchurch mutation had little noticeable effect on the propagation of tau pathology but appeared to heighten microglial responses (Chen et al., 2024).

APOE3Ch knock-in, floxed (CureAlz) x APPPS1. To study the effects of the APOE Christchurch mutation in the context of amyloidosis, knock-in mice homozygous for the human APOE3 allele with or without the mutation were intercrossed with APPPS1 mice, which carry transgenes for human APP and PSEN1 with AD-linked mutations. Compared with mice expressing wild-type APOE3, mice with the Christchurch mutation displayed slight reductions in amyloid pathology but increased microglial clustering and microglial reactivity around plaques (Chen et al., 2024).

APOE3Ch knock-in, floxed (CureAlz) x APPPS1, tau intracerebral injection. To study the effects of the APOE Christchurch mutation on tau seeding and spreading in the context of amyloidosis, tau fibrils from an AD brain were injected into the brains of mice with humanized APOE3 genes with or without the mutation, in which amyloid deposition was driven by APP and PSEN1 transgenes with AD-linked mutations (Chen et al., 2024). The APOE Christchurch mutation partially protected against the induction and spread of plaque-associated tau pathology and neuronal damage. The Christchurch mutation also attenuated amyloid pathology in the brains of mice who had received intracerebral injections of tau fibrils, while enhancing microgliosis in the vicinity of fibrillar plaques.

APOE4Ch knock-in, floxed (Gladstone). In these knock-in mice, the coding region of the mouse Apoe gene was replaced with the human APOE4 sequence flanked by LoxP sites and containing the Christchurch mutation (Nelson et al., 2023). Expression of the humanized gene is under the control of endogenous mouse regulatory elements.

APOE4Ch knock-in, floxed (Gladstone) x PS19. To study the effects of the Christchurch mutation on tau pathology in the context of APOE4, APOE4 knock-in mice with or without the Christchurch mutation were intercrossed with PS19 mice, which carry a human MAPT transgene with the P301S mutation linked to frontotemporal dementia (Nelson et al., 2023). Compared with APOE3, APOE4 exacerbated pathology in PS19 mice—increasing levels of “pathological” tau, decreasing hippocampal volume, and increasing gliosis. The Christchurch mutation, when homozygous, fully protected against these effects of APOE4 and showed a gene-dose-dependent effect on proportions of populations of neural cells identified through transcriptomic analyses—increasing disease-protective neuronal and glial subpopulations and decreasing disease-associated glial subpopulations.

ApoeCh. In the ApoeCh mouse, the Christchurch mutation was introduced into the mouse Apoe gene, preserving the species match between the ApoE protein and its murine receptors (Tran et al., 2025). Thus far, only peripheral phenotypes have been described. At 4 months of age, levels of plasma cholesterol were elevated in homozygous ApoeCh mice compared with wild-type mice, and this effect was primarily driven by males. Levels of plasma triglyceride and very low-density lipid did not differ between the genotypes.

ApoeCh x 5xFAD. In order to study the effects of the Christchurch mutation in the context of amyloid pathology, ApoeCh mice were crossed with 5xFAD mice (Tran et al., 2025). The Christchurch mutation appeared to promote a disease-associated state in microglia surrounding amyloid plaques, accompanied by reductions in plaque load and plaque-associated neuron damage.

ApoeCh x PS19. In order to study the effects of the Christchurch mutation in the context of tau pathology, ApoeCh mice were crossed with PS19 mice (Tran et al., 2025). In this tauopathy model, the Christchurch mutation promoted a homeostatic state in microglia and counteracted tau-induced changes in gene expression in oligodendrocytes, without decreasing—and, in some cases, exacerbating—certain disease-associated post-translational modifications of tau.

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References

Research Models Citations

1. APOE3 Knock-In, floxed (CureAlz)
2. APOE3Ch knock-in, floxed (CureAlz) x APPPS1, tau intracerebral injection
3. APOE3Ch (Cornell)
4. APOE3 knock-in (Cornell)
5. APOE3Ch (Cornell) x PS19
6. Tau P301S (Line PS19)
7. APOE3Ch knock-in, floxed (CureAlz), tau intracerebral injection
8. APOE3Ch knock-in, floxed (CureAlz)
9. APOE3Ch knock-in, floxed (CureAlz) x APPPS1
10. APPPS1
11. APOE4Ch knock-in, floxed (Gladstone)
12. APOE4Ch knock-in, floxed (Gladstone) x PS19
13. APOE4 knock-in, floxed (Gladstone)
14. ApoeCh
15. ApoeCh x 5xFAD
16. 5xFAD (C57BL6)
17. ApoeCh x PS19

Mutations Citations

1. APOE R154S (Christchurch)
2. MAPT P301S

Paper Citations

1. Chen Y, Song S, Parhizkar S, Lord J, Zhu Y, Strickland MR, Wang C, Park J, Tabor GT, Jiang H, Li K, Davis AA, Yuede CM, Colonna M, Ulrich JD, Holtzman DM. APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread. Cell. 2024 Jan 18;187(2):428-445.e20. Epub 2023 Dec 11 PubMed.
2. Naguib S, Lopez-Lee C, Torres ER, Lee SI, Zhu J, Zhu D, Ye P, Norman K, Zhao M, Wong MY, Ambaw YA, Muñoz-Castañeda R, Wang W, Patel T, Bhagwat M, Norinsky R, Mok SA, Walther TC, Farese RV Jr, Luo W, Sinha SC, Wu Z, Fan L, Gong S, Gan L. The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway. Immunity. 2025 Jun 18; Epub 2025 Jun 18 PubMed.
3. Nelson MR, Liu P, Agrawal A, Yip O, Blumenfeld J, Traglia M, Kim MJ, Koutsodendris N, Rao A, Grone B, Hao Y, Yoon SY, Xu Q, De Leon S, Choenyi T, Thomas R, Lopera F, Quiroz YT, Arboleda-Velasquez JF, Reiman EM, Mahley RW, Huang Y. The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Nat Neurosci. 2023 Dec;26(12):2104-2121. Epub 2023 Nov 13 PubMed.
4. Tran KM, Kwang NE, Butler CA, Gomez-Arboledas A, Kawauchi S, Mar C, Chao D, Barahona RA, Da Cunha C, Tsourmas KI, Shi Z, Wang S, Collins S, Walker A, Shi KX, Alcantara JA, Neumann J, Duong DM, Seyfried NT, Tenner AJ, LaFerla FM, Hohsfield LA, Swarup V, MacGregor GR, Green KN. APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology. Mol Neurodegener. 2025 Jan 22;20(1):9. PubMed.

Further Reading