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

The APOE Christchurch variant captured the attention of Alzheimer’s researchers when it was identified as a candidate protective factor 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. Her brain was laden with amyloid plaques, but tau pathology was remarkably restricted (Arboleda-Velasquez et al., 2019; Sepulveda-Falla et al., 2022).

This model was developed to study the effects of the APOE Christchurch mutation on tau seeding and spreading in the context of amyloidosis. Intracerebral injection of tau fibrils derived from AD brains was previously shown to induce tau pathology around amyloid plaques in mouse models, both at the injection site and in synaptically connected regions (He et al., 2018; Leyns et al., 2019; see Dec 2017 news). Here, tau fibrils from an AD brain were injected into the brains of mice with humanized APOE3 genes with or without the Christchurch 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.

APOE3 knock-in, APOE3Ch knock-in, and APPPS1 mice were intercrossed to generate mice hemizygous for the APP and PSEN1 transgenes and homozygous for either APOE3 with the Christchurch mutation (APP/PS1:APOE3Ch) or wild-type human APOE3 (APP/PS1:APOE3). Tau fibrils extracted from the brain of an AD subject (Braak stage VI) were unilaterally injected into the dentate gyri and overlying cortices of 6-month-old female mice, and the animals were killed 3.5 months post-injection.

Amyloid pathology

The APOE Christchurch mutation attenuated amyloid pathology in the brains of mice who had received intracerebral injections of AD tau fibrils. Plaque pathology was evaluated using the fluorescent dye X34, which labels β-sheet structures, and an antibody directed against Aβ. Plaque number and burden (percent area occupied by plaques) were reduced in APP/PS1:APOE3Ch brains compared with APP/PS1:APOE3 brains, regardless of whether X34 or immunolabeling was used to visualize plaques. While Aβ-immunoreactive plaques were smaller in the Christchurch carriers, APOE genotype did not significantly affect the size of X34-labeled plaques. 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 less in the Christchurch carriers.

Amyloid-dependent tau seeding and spreading

In the current model, tau pathology was evaluated as immunoreactivity to AT8, a monoclonal antibody that detects “pretangles,” mature neurofibrillary tangles, and neuropil threads. Three months after injection of AD-derived tau fibrils, plaque-associated tau pathology was observed at the injection sites and in connected regions. The Christchurch mutation partially protected against the induction and spread of tau pathology: The burdens of AT8-immunoreactive tau were lower in APP/PS1:APOE3Ch mice, compared with APP/PS1:APOE3 mice, in the dentate gyri, CA1, entorhinal cortices, and somatosensory cortices, both ipsilateral and contralateral to the injection site. Christchurch carriers also displayed less AT8 immunoreactivity per plaque.

Plaque-associated neuronal damage

Markers of peri-plaque neuronal damage were attenuated in the Christchurch carriers. Compared with APP/PS1:APOE3 mice, APP/PS1:APOE3Ch mice had lower levels of BACE1, which accumulates in dystrophic neurites, and elevated levels of the synaptic markers synapsin and PSD95 in the vicinity of plaques.

Gliosis

The Christchurch mutation enhanced microgliosis in the vicinity of fibrillar plaques. Compared with APP/PS1:APOE3 mice, APP/PS1:APOE3Ch mice showed increased clustering of microglia around X34-positive plaques in the hippocampi and cortices both ipsilateral and contralateral to the sites of injection of tau fibrils. Christchurch carriers also displayed increased immunostaining for CD68, a lysosomal protein often used as a  marker of phagocytic microglia (reviewed by Hopperton et al., 2018), but decreased staining for TMEM119, a marker for homeostatic microglia (Keren-Shaul et al., 2017; Krasemann et al., 2017; Zhou et al., 2020), in the vicinity of plaques.

Astrogliosis—assessed as the burden of GFAP immunoreactivity—was attenuated in the hippocampi and cortices of APP/PS1:APOE3Ch mice, compared with APP/PS1:APOE3, both ipsilateral and contralateral to the tau-fibril injection sites.

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.

Tau fibrils extracted from the brain of an AD subject were unilaterally injected into the dentate gyri and overlying cortices of 6-month-old female 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. 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).

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. APP K670_M671delinsNL (Swedish)
4. PSEN1 L166P
5. MAPT P301S

News Citations

1. Aβ Plaques: Breeding Ground for Toxic Tau? 6 Dec 2017

Research Models Citations

1. APOE3 Knock-In, floxed (CureAlz)
2. APOE3Ch 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
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

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Further Reading