Species: Mouse
Genes: Apoe, MAPT
Mutations: APOE R154S (Christchurch), MAPT P301S
Modification: Apoe: Knock-In; MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia
Strain Name: N/A
Genetic Background: C57BL/6J
Availability: ApoeCh mice are available for pre-order from The Jackson Laboratory, Stock# 039301. Estimated to begin distribution March, 2026. PS19 mice on a C57BL/6J background are available from The Jackson Laboratory: Stock# 024841.
RRID: IMSR_JAX:039301; IMSR_JAX:024841

Summary

The APOE Christchurch variant was identified as a candidate protective factor against Alzheimer’s disease in a carrier of the PSEN1 “Paisa” mutation—the most common cause of familial autosomal dominant AD—who was homozygous for the Christchurch variant on an APOE3 background. This individual remained cognitively healthy for decades after the expected age-of-onset of cognitive decline in her family and had a high amyloid burden but restricted tau pathology at the time of her death from melanoma (Arboleda-Velasquez et al., 2019; Sepulveda-Falla et al., 2022).

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). ApoeCh mice have the Christchurch mutation knocked into the mouse Apoe gene, preserving the species match between the ApoE protein and its murine receptors. PS19 mice carry a human MAPT transgene with the P310S mutation linked to frontotemporal dementia. 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.

ApoeCh and PS19 mice were intercrossed to generate the following four genotypes: (i) wild-type (WT), (ii) homozygous for the Apoe Christchurch allele (ApoeCh), (iii) hemizygous for the MAPT P301S transgene (PS19) and (iv) homozygous for the Apoe Christchurch allele and hemizygous for the MAPT P301S transgene (PS19;ApoeCh). Mice were studied at 5 and 9 months of age. Both males and females were used in these studies.

Expression of Apoe mRNA and ApoE protein

The four genotypes did not differ with regard to levels of Apoe mRNA or ApoE protein, as determined by spatial transcriptomics and spatial proteomics, respectively, performed on sections from 9-month-old mice. ELISA confirmed similar levels of ApoE protein in detergent-soluble fractions from the cortices of the four genotypes, and dot-blot analysis confirmed similar protein levels in detergent-insoluble fractions.

Peripheral phenotypes

At 9 months of age, carriers of the MAPT transgene were smaller than their non-transgenic counterparts (the average body weights of PS19 mice were less than WT mice, and PS19;ApoeCh mice weighed less than ApoeCh mice). The Christchurch mutation did not affect body weight in mice of this age (the average body weights of WT and ApoeCh mice were similar, as were the body weights of PS19 and PS19;ApoeCh mice).

Tau

PS19 mice exhibit age-dependent post-translational modifications of tau like those seen in Alzheimer’s disease. The Christchurch mutation may have exacerbated some aspects of tau pathology in these mice.

Immunoreactivity to monoclonal antibody AT8, a common marker of tau pathology, was assessed both immunohistochemically and by western blot. The MAPT P301S transgene increased AT8 immunostaining in the dentate gyrus and piriform cortex—apparent by 5 months when comparing PS19 with  WT mice, and by 9 months when comparing PS19;ApoeCh with ApoeCh mice. The Christchurch mutation did not affect the degree of AT8 immunoreactivity, assessed either immunohistochemically or in western blots of cortical homogenates. Nor did the Christchurch mutation affect the number of inclusions stained using monoclonal antibody MC-1, which recognizes a tau conformation that precedes the appearance of neurofibrillary tangles.

Phosphorylation of tau at threonine-231 (p-tau231) is another marker of tau pathology. Plasma p-tau231(Ashton et al., 2021) and CSF p-tau231 (Suárez-Calvet et al., 2020) have emerged as biomarkers for presymptomatic AD, and multiple studies have shown that levels of p-tau231 remain elevated in the CSF of individuals with symptomatic AD (see AlzBiomarker meta-analysis). In the brain, p-tau231 is associated with neurofibrillary tangles and neuropil threads (Wennström et al., 2022). Levels of p-tau231, measured by electrochemiluminescence, were elevated in soluble and insoluble fractions of the cortices and hippocampi of 9-month-old mice carrying the MAPT P301S transgene, with further increases in the brains of PS19 mice carrying the Christchurch mutation. Analysis of spatial proteomic data supported increased p-tau231 and other phospho-tau species (p-tau396, p-tau214, and p-tau404) in neurons of PS19;ApoeCh compared with PS19 brains. However, it should be noted that levels of phospho-tau species were not normalized to levels of total tau in these analyses, making it difficult to conclude from these data that the Christchurch mutation led to specific elevations in these markers of tauopathy.

Gliosis

The Apoe Christchurch mutation decreased markers of gliosis in carriers of the MAPT P301S transgene, studied at 9 months of age.

Spatial proteomics showed reduced expression of the astrocytic markers GFAP, ApoE, and vimentin in the brains of PS19;ApoeCh mice compared with PS19 mice, and immunohistochemistry confirmed a lower burden  of GFAP (percent volume occupied by GFAP immunoreactivity) in the dentate gyrus of Christchurch carriers. Additionally, the brains of PS19;ApoeCh mice contained a smaller proportion of cells with transcriptomic profiles characteristic of disease-associated astrocytes than did the brains of PS19 mice, as determined by spatial transcriptomics.

Similarly, there was a smaller proportion of cells with transcriptomic profiles characteristic of disease-associated microglia (DAM) in the brains of PS19;ApoeCh than in the brains of PS19 mice. Spatial proteomics supported the transcriptomic findings—showing reduced expression of the DAM-related proteins CD11c, CD68, and TYROBP in the Christchurch carrriers. Finally, immunostaining for the microglial marker Iba1 was decreased in the dentate gyrus of PS19;ApoeCh mice, compared with PS19 mice.

Neuronal damage

In 9-month-old mice, the MAPT P301S transgene led to elevated levels of plasma neurofilament light chain (NfL), considered a marker of neuronal damage. The Christchurch mutation did not protect against this increase in NfL.

Synaptic markers

There are hints that the Christchurch mutation might protect synapses in the context of tauopathy, but the evidence available thus far is inconclusive. Spatial transcriptomic analysis of the CA1 region of the hippocampi of 9-month-old mice showed up-regulation of several genes involved in synaptic function and plasticity in PS19;ApoeCh compared with the other three genotypes. However, synapse number in CA1—assessed as the co-localization of the pre-synaptic marker Bassoon and the post-synaptic marker Homer1, imaged with super-resolution microscopy—did not differ between PS19;ApoeCh and the other three genotypes (although there were fewer synapses in PS19 mice than WT mice).

Behavior

It had previously been reported that PS19 mice on a C57BL/6 background show hyperactivity and reduced anxiety in the open field, compared with non-transgenic littermate controls (14-week-old males: Takeuchi et al., 2011; 9-month-old males and females: Patel et al., 2022). In the current study, neither velocity (activity) nor time in the center of the open field (anxiety) differed between the four genotypes at 5 or 9 months of age (Tran et al., 2025).

Time spent in the open arms of the elevated plus maze (EPM) is also used to measure anxiety in mice (with increased time reflecting decreased anxiety). The 14-week-old male PS19 mice mentioned above also showed reduced anxiety in this behavioral assay (Takeuchi et al., 2011). In the current study, 5-month-old PS19;ApoeCh mice spent more time in the open arms than WT or ApoeCh mice, but PS19 animals did not differ from the other groups. At 9 months, consistent with an anxiolytic effect of the MAPT P301S transgene, PS19 and PS19;ApoeCh mice spent more time in the open arms of the EPM than WT and ApoeCh mice, respectively. The Christchurch mutation did not affect this measure.

Hindlimb clasping, considered to be an indicator of neurodegeneration, did not differ among the four genotypes at 5 months of age. At 9 months, carriers of the MAPT transgene had higher clasping scores (indicative of a more severe phenotype) than  WT mice; the scores of ApoeCh mice were intermediate between  WT animals and MAPT carriers and did not differ from the other three genotypes. The Christchurch mutation did not protect against this behavioral marker of neurodegeneration (i.e., clasping scores in PS19;ApoeCh mice did not differ from PS19 mice), consistent with its lack of effect on levels of plasma NfL, a fluid marker for neuron damage.

Other

Spatial transcriptomics revealed differential expression of genes in oligodendrocytes of the corpus callosum, when PS19 mice were compared with WT mice—with some genes upregulated (Tmsb4x, Apoe, Scd2, and Pllp) and some downregulated (Sgk1, Gsn, and Ptg) in the tauopathy model. Apoe Christchurch opposed these changes in expression in PS19 mice. Additionally, the Christchurch mutation led to increased expression of other genes in oligodendrocytes independently of the MAPT P301S transgene, including Mbp, Myrf and Slc44a1. Spatial proteomics confirmed increased expression of myelin basic protein (MBP) in PS19;ApoeCh mice compared with PS19.

Modification details

ApoeCh: CRISPR/Cas9 editing was used to introduce a CGG to TCT missense mutation in the mouse Apoe gene, leading to an arginine-to-serine substitution at amino acid 146 (numbering scheme including the signal peptide) in the mouse ApoE protein—equivalent to amino acid 154 in human ApoE.

PS19: PS19 transgenic mice express mutant human microtubule-associated protein tau (MAPT), driven by the mouse prion protein (Prnp) promoter. The transgene encodes the disease-associated P301S mutation and includes four microtubule-binding domains and one N-terminal insert (4R/1N).

Related Models

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.

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).

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.

Phenotype Characterization

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References

Mutations Citations

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

Research Models Citations

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

AlzAntibodies Citations

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

Biomarker Meta Analysis Citations

1. Alzheimer's Disease vs Control: tau-p231 (CSF) 30 Jun 2021

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. 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.
4. Ashton NJ, Pascoal TA, Karikari TK, Benedet AL, Lantero-Rodriguez J, Brinkmalm G, Snellman A, Schöll M, Troakes C, Hye A, Gauthier S, Vanmechelen E, Zetterberg H, Rosa-Neto P, Blennow K. Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology. Acta Neuropathol. 2021 May;141(5):709-724. Epub 2021 Feb 14 PubMed.
5. Suárez-Calvet M, Karikari TK, Ashton NJ, Lantero Rodríguez J, Milà-Alomà M, Gispert JD, Salvadó G, Minguillon C, Fauria K, Shekari M, Grau-Rivera O, Arenaza-Urquijo EM, Sala-Vila A, Sánchez-Benavides G, González-de-Echávarri JM, Kollmorgen G, Stoops E, Vanmechelen E, Zetterberg H, Blennow K, Molinuevo JL, ALFA Study. Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer's continuum when only subtle changes in Aβ pathology are detected. EMBO Mol Med. 2020 Dec 7;12(12):e12921. Epub 2020 Nov 10 PubMed.
6. Wennström M, Janelidze S, Nilsson KP, Netherlands Brain Bank, Serrano GE, Beach TG, Dage JL, Hansson O. Cellular localization of p-tau217 in brain and its association with p-tau217 plasma levels. Acta Neuropathol Commun. 2022 Jan 6;10(1):3. PubMed.
7. Takeuchi H, Iba M, Inoue H, Higuchi M, Takao K, Tsukita K, Karatsu Y, Iwamoto Y, Miyakawa T, Suhara T, Trojanowski JQ, Lee VM, Takahashi R. P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating. PLoS One. 2011;6(6):e21050. PubMed.
8. Patel H, Martinez P, Perkins A, Taylor X, Jury N, McKinzie D, Lasagna-Reeves CA. Pathological tau and reactive astrogliosis are associated with distinct functional deficits in a mouse model of tauopathy. Neurobiol Aging. 2022 Jan;109:52-63. Epub 2021 Sep 20 PubMed.
9. 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.
10. 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.
11. 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.

External Citations

1. The Jackson Laboratory, Stock# 039301
2. The Jackson Laboratory: Stock# 024841

Further Reading

No Available Further Reading