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: To request APOE3Ch knock-in, floxed (CureAlz) mice, please contact David Holtzman.

Summary

The APOE Christchurch variant gained the attention of Alzheimer’s researchers when it was identified as a candidate protective factor against Alzheimer’s disease. This rare variant was found in a Colombian woman who carried the PSEN1 “Paisa” mutation—the most common cause of familial autosomal dominant AD—but remained cognitively healthy for decades after the expected age-of-onset of cognitive decline in her family (Arboleda-Velasquez et al., 2019). PET imaging studies performed during her life revealed a high burden of amyloid plaques but little tau pathology (Arboleda-Velasquez et al., 2019), and these findings were confirmed by histological studies performed after her death from melanoma (Sepulveda-Falla et al., 2022). This remarkably resilient individual carried two copies of the Christchurch variant on an APOE3 background.

To study the effects of the Christchurch mutation on tau seeding and spreading, tau fibrils from the brain of a human AD subject were injected into the brains of knock-in mice homozygous for the human APOE3 allele with or without the Christchurch mutation (Chen et al., 2024). In the absence of amyloid pathology, the Christchurch mutation had little noticeable effect on the propagation of tau pathology but appeared to heighten microglial responses, as described below. However, the Christchurch mutation partially suppressed tau seeding and spreading in the context of amyloid pathology, as discussed here.

Effects of the Christchurch mutation on amyloid-independent tau seeding and spreading

Tau fibrils extracted from the brain of an AD subject were unilaterally injected into the dentate gyri and overlying cortices of 9.5-month-old mice. Six months later, the brains of these mice were assessed histologically for tau pathology and microglial reactivity.

Tau pathology was evaluated as immunoreactivity to AT8. This monoclonal antibody detects “pretangles,” mature neurofibrillary tangles, and neuropil threads and is a common marker of tauopathy. AT8 immunoreactivity at the primary injection site and at seven propagation sites did not differ when comparing the brains of knock-in mice homozygous for human APOE3 with the Christchurch mutation (APOE3Ch) to those of mice homozygous for wild-type APOE3 (APOE3). (The seven propagation sites—regions connected to the hippocampus—were the ventral retrosplenial cortex [RSPv], entorhinal cortex [ERC], and hypothalamus [HYP] ipsilateral to the injection site, and the dentate gyrus, RSPv, ERC, and HYP contralateral to the injection site.)

Microglial reactivity was evaluated as immunoreactivity for CD68, a lysosomal marker believed to reflect phagocytic activity (Walker and Lue, 2015). CD68 immunoreactivity was elevated at the primary injection site, the contralateral dentate gyrus, and bilaterally in the RSPv of APOE3Ch mice, compared with APOE3 mice.

Modification details

Tau fibrils from an AD brain were injected into the brains of APOE3Ch knock-in, floxed (CureAlz) mice, which carry a humanized APOE (ε3 allele) coding sequence with the Christchurch mutation, flanked by loxP sites. Expression of the humanized gene is under the control of endogenous mouse regulatory elements. (For comparison, tau fibrils were also injected into the brains of knock-in mice expressing wild-type human APOE3.)

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) 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.

Phenotype Characterization

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References

Mutations Citations

1. APOE R154S (Christchurch)
2. PSEN1 E280A (Paisa)
3. MAPT P301S

Research Models Citations

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

AlzAntibodies Citations

1. Tau (AT8); Phospho Tau (Ser 202, Thr 205) 18 May 2022

Paper Citations

1. Arboleda-Velasquez JF, Lopera F, O'Hare M, Delgado-Tirado S, Marino C, Chmielewska N, Saez-Torres KL, Amarnani D, Schultz AP, Sperling RA, Leyton-Cifuentes D, Chen K, Baena A, Aguillon D, Rios-Romenets S, Giraldo M, Guzmán-Vélez E, Norton DJ, Pardilla-Delgado E, Artola A, Sanchez JS, Acosta-Uribe J, Lalli M, Kosik KS, Huentelman MJ, Zetterberg H, Blennow K, Reiman RA, Luo J, Chen Y, Thiyyagura P, Su Y, Jun GR, Naymik M, Gai X, Bootwalla M, Ji J, Shen L, Miller JB, Kim LA, Tariot PN, Johnson KA, Reiman EM, Quiroz YT. Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019 Nov;25(11):1680-1683. Epub 2019 Nov 4 PubMed.
2. Sepulveda-Falla D, Sanchez JS, Almeida MC, Boassa D, Acosta-Uribe J, Vila-Castelar C, Ramirez-Gomez L, Baena A, Aguillon D, Villalba-Moreno ND, Littau JL, Villegas A, Beach TG, White CL 3rd, Ellisman M, Krasemann S, Glatzel M, Johnson KA, Sperling RA, Reiman EM, Arboleda-Velasquez JF, Kosik KS, Lopera F, Quiroz YT. Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer's dementia. Acta Neuropathol. 2022 Sep;144(3):589-601. Epub 2022 Jul 15 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. Walker DG, Lue LF. Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains. Alzheimers Res Ther. 2015 Aug 19;7(1):56. PubMed.
5. 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.
6. 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.
7. 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