Species: Mouse
Genes: APOE, APP, PSEN1
Mutations: APOE R154S (Christchurch), APP K670_M671delinsNL (Swedish), PSEN1 L166P
Modification: APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL/6J
Availability: To request APOE3Ch knock-in, floxed (CureAlz) mice, please contact David Holtzman. APPPS1mice are available through Mathias Jucker.

Summary

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 human APP and PSEN1 transgenes with AD-linked mutations. Compared with mice expressing the wild-type APOE3 allele, mice carrying the Christchurch mutation displayed reductions in amyloid pathology but increased microglial clustering and reactivity around plaques (Chen et al., 2024).

The mice described below were homozygous for the APOE3 alleles (either wild-type or Christchurch) and hemizygous for the APP and PSEN1 transgenes.

Amyloid pathology

Plaque pathology was assessed using the fluorescent dye X34, which labels β-sheet structures, and an antibody directed against Aβ. At 6 months of age, APP/PS1:APOE3Ch mice had slightly lower fibrillar-plaque burdens (i.e., percent area occupied by X34-positive profiles) than APP/PS1:APOE3 mice, and plaques were, on average, smaller in the Christchurch carriers. The genotypes were similar with regard to Aβ-immunoreactive plaques at this age. X34-labled fibrillar plaque cores were surrounded by halos of immunoreactive Aβ, and the amount of Aβ within a 15-µm radius of the plaque core was similar in the two genotypes. Only female mice were examined.

Glial phenotypes

The Christchurch mutation enhanced microgliosis in the vicinity of fibrillar plaques. At 6 months of age, APP/PS1:APOE3Ch mice showed increased clustering of microglia around X34-positive plaques, compared with APP/PS1:APOE3 mice. Two markers of microglial reactivity, CD68 and ApoE itself, were elevated in plaque-associated microglia of APP/PS1:APOE3Ch mice, although staining for CLEC7A, another putative marker of reactive microglia, did not differ between mice expressing APOE3-Christchurch and wild-type APOE3. Immunostaining for TMEM119, a marker of homeostatic microglia, also did not differ between the APOE3 genotypes.

Staining for the astrocytic marker GFAP did not differ between APP/PS1:APOE3Ch and APP/PS1:APOE3 mice.

Only female mice were used for the immunohistochemical study of glial markers.

Behavioral phenotypes

APP/PS1:APOE3Ch and APP/PS1:APOE3 mice performed similarly in tests of spatial working memory (spontaneous alternation in the Y-maze) and associative learning and memory (cued and contextual fear conditioning), when tested between 4 and 6 months of age. However, it should be noted that the APP and PS1 transgenes did not impair performance in these tests at this age (i.e., APP/PS1:APOE3Ch and APP/PS1:APOE3 mice did not differ from APOE3Ch or APOE3 knock-in mice, respectively).

Applications of the model

To study the effects of the Christchurch mutation on tau seeding and spreading in the context of amyloidosis, APP/PS1:APOE3Ch and APP/PS1:APOE3 mice received intracerebral injections of tau fibrils from an AD brain (see Related Models below).

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—was 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.

APPPS1 mice carry human transgenes for APP and PSEN1 bearing the AD-linked Swedish and L166P mutations, respectively, both under the control of the Thy1 promoter.

APPPS1 mice were first intercrossed with APOE3 knock-in mice to generate APP/PS1:APOE3 mice. APP/PS1:APOE3 were then intercrossed with APOE3Ch knock-in mice to generate APP/PS1:APOE3Ch mice.

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). 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, 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.

Phenotype Characterization

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References

Mutations Citations

1. APOE R154S (Christchurch)
2. APP K670_M671delinsNL (Swedish)
3. PSEN1 L166P
4. MAPT P301S

Research Models Citations

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

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