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: Available through Li Gan. Requestors must complete a standard MTA with Weill Cornell Medicine.

Summary

Since the identification of the APOE Christchurch variant as a candidate protective factor against Alzheimer’s disease, several mouse models have been created to study the effects of this variant in healthy animals and in animals with Alzheimer’s-like pathology. Animals carrying the Christchurch variant in humanized APOE alleles (both APOE3 and APOE4) and in the murine Apoe gene are available.

APOE3Ch (Cornell) mice express human APOE3 with the Christchurch mutation, under the control of mouse regulatory elements (Naguib et al., 2025). Initial characterization of these mice compared them with knock-in mice expressing wild-type human APOE3. The APOE knock-in mice have also been crossed with PS19 mice to study the effects of the Christchurch mutation in the context of tauopathy.

The following description refers to mice homozygous for either APOE3-Christchurch (APOE3Ch) or wild-type human APOE3 (APOE3). Studies were performed on male mice 9- to 10-months-old, unless stated otherwise.

ApoE expression

Levels of ApoE protein in the frontal cortex, evaluated in western blots, did not differ between mice expressing wild type human APOE3 and APOE3-Christchurch. Nor did levels of plasma ApoE differ between the two genotypes. (Both males and females were used for the measurement of cortical ApoE, but only males were used to measure plasma ApoE.)

Synaptic markers

Levels of the presynaptic marker synaptophysin and the postsynaptic marker PSD95—evaluated by western blot in frontal cortical lysates and by immunofluorescence in hippocampal CA1, respectively—did not differ between APOE3 and APOE3Ch mice.

Neural activity

Network activity was monitored in freely moving mice using a multi-electrode array to record local field potentials in the somatosensory cortex, visual cortex, hippocampal CA1, and the dentate gyrus. APOE3 and APOE3Ch mice did not differ with regards to theta or gamma power averaged across regions or in the dentate gyrus (the other three regions were not reported upon separately).

Glia

APOE3 and APOE3Ch mice did not differ with regards to microglial (Iba1 immunofluorescence, cell size, and cell morphology) or astrocytic (GFAP immunofluorescence) markers in CA1.

Levels of myelin basic protein in the hippocampus—evaluated by immunofluorescence—did not differ between APOE3 and APOE3Ch mice.

Modification details

Human APOE3-R154S cDNA with a poly A tail was inserted immediately upstream of the ATG start codon of the mouse Apoe gene. Expression of human APOE3 is controlled by the mouse Apoe promoter and regulatory elements, and the mouse Apoe gene is inactivated.

Applications of the model

Primary microglial cultures have been used to study the effects of the Christchurch mutation on microglial responses to Aβ and tau (Naguib et al., 2025).

Cultures were prepared from the cortices of 1- to 3-day-old APOE3 and APOE3Ch mouse pups.

Transcriptomic responses to Aβ monomers. Compared with APOE3 microglia, APOE3Ch microglia down-regulated genes involved in interferon signaling, cytokine signaling, and innate immune responses, after exposure to Aβ monomers. Up-regulated genes included Rho-GTPases and genes involved in collagen synthesis.

Transcriptomic responses to tau. Compared with APOE3 microglia, APOE3Ch microglia up-regulated genes involved in RNA processing and transcription, after exposure to tau fibrils. Genes involved in interferon signaling were down-regulated in tau-exposed APOE3Ch microglia compared with APOE3 cells. Ingenuity pathway analysis predicted that the upstream regulators of interferon signaling cGAS (cyclic GMP-AMP synthase) and STING (stimulator of interferon genes) would be inhibited in tau-treated APOE3Ch microglia compared with APOE3 microglia. Relative inhibition of the cGAS-STING-interferon pathway in APOE3Ch microglia was confirmed at the protein level: When activated, STING moves from the endoplasmic reticulum to the Golgi apparatus, and co-localization of STING and the Golgi marker GM130 was used as a marker for STING activation. There was less co-localization of STING with GM130 in tau-treated APOE3Ch microglia, compared with tau-treated APOE3 microglia. (The cGAS-STING-interferon pathway was of particular interest to Gan’s group, who had previously observed activation of this pathway in microglia in AD brains and in the PS19 mouse model of tauopathy and went on to show that that genetic ablation or pharmacological inhibition of cGAS restored synaptic plasticity and cognitive function in the mice [Udeochu et al., 2023; see 26 Apr 2023 news].)

Tau uptake and processing by primary microglia. A pulse-chase assay was employed to examine the effect of the Christchurch mutation on tau handling by microglia. APOE3Ch microglia showed slightly greater uptake of tau fibrils than did APOE3 microglia. The Christchurch carriers also showed more rapid disposition of the ingested tau.

Related Models

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). 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 (Chen et al., 2024). Peripheral dyslipidemia has been reported. Bone marrow-derived macrophages (BMDMs) from mice homozygous for the human APOE3-Christchurch allele show enhanced uptake of tau fibrils, degrade these fibrils more quickly, and release less tau than BMDMs from knock-in mice homozygous for the wild-type human APOE3 allele. Under basal conditions, APOE3Ch and APOE3 BMDMs did not differ in their uptake of Aβ fibrils, but tau fibrils enhanced the uptake of Aβ by APOE3Ch BMDMs, while having no effect on Aβ uptake by APOE3 BMDMs.

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 a reduction 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.

COMMENTS / QUESTIONS

No Available Comments

Make a comment or submit a question

To make a comment you must login or register.

References

Mutations Citations

1. APOE R154S (Christchurch)
2. MAPT P301S

Research Models Citations

1. APOE3 knock-in (Cornell)
2. APOE3Ch (Cornell) x PS19
3. Tau P301S (Line PS19)
4. APOE3Ch (Cornell)
5. APOE3Ch knock-in, floxed (CureAlz)
6. APOE3 Knock-In, floxed (CureAlz)
7. APOE3Ch knock-in, floxed (CureAlz), tau intracerebral injection
8. APOE3Ch knock-in, floxed (CureAlz) x APPPS1
9. APPPS1
10. APOE3Ch knock-in, floxed (CureAlz) x APPPS1, tau intracerebral injection
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

News Citations

1. By Unleashing Microglial cGAS, Tau STINGs Neurons 26 Apr 2023

Paper Citations

1. 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.
2. Udeochu JC, Amin S, Huang Y, Fan L, Torres ER, Carling GK, Liu B, McGurran H, Coronas-Samano G, Kauwe G, Mousa GA, Wong MY, Ye P, Nagiri RK, Lo I, Holtzman J, Corona C, Yarahmady A, Gill MT, Raju RM, Mok SA, Gong S, Luo W, Zhao M, Tracy TE, Ratan RR, Tsai LH, Sinha SC, Gan L. Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience. Nat Neurosci. 2023 May;26(5):737-750. Epub 2023 Apr 24 PubMed.
3. 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.
4. 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.
5. 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

No Available Further Reading