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Cited by 18Alzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis ResearchDementia and Cognitive Impairment Research

The DOI matches its Crossref record; 92 of the 93 references it cites were found in a registry or an index; none of the 32 sources its claims cite is checked for support yet.

Human MAPT knockin mouse models of frontotemporal dementia for the neurodegenerative research community

Open access
Morito, Takahiro, Qi, Mohan, Kamano, Naoko, Sasaguri, Hiroki, Bez, Sumi, Foiani, Martha, Duff, Karen, Benner, Seico, Endo, Toshihiro, Hama, Hiroshi, Kurokawa, Hiroshi, Miyawaki, Atushi, Mizuma, Hiroshi, Sahara, Naruhiko, Shimojo, Masafumi, Higuchi, Makoto, Saido, Takaomi C., Watamura, Naoto·2025·Cell Reports Methods
DOI 10.1016/j.crmeth.2025.101024PMC PMC12256944
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Abstract

Existing models of frontotemporal dementia (FTD) may not fully recapitulate the pathophysiology of the disease. To generate more pathophysiologically relevant FTD models, we engineered MAPT knockin mouse lines carrying triple mutations, among which the MAPT P301S;Int10+3;S320F line exhibited robust tau pathology starting before 6 months of age. Severe tau accumulation was predominantly observed in the thalamus, hypothalamus, and amygdala with milder involvement of the cortex and hippocampus, leading to synaptic loss, brain atrophy, and FTD-like behavioral abnormalities. Crossbreeding MAPT P301S;Int10+3;S320F mice with App knockin, App NL-G-F , mice markedly enhanced tau pathology in the cortex and hippocampus, highlighting the interplay between β-amyloid and tau. These findings establish the mutant mice as valuable models for investigating the mechanisms underlying FTD and other tauopathies, providing a relevant platform for in vivo drug screening.

Overview

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TL;DR

The authors generated triple-mutant human MAPT knockin mouse lines and identified MAPTP301S;Int10+3;S320F as a rapidly progressing FTD model with tau pathology before 6 months, synaptic loss, brain atrophy, and FTD-like behaviors. Crossbreeding with AppNL-G-F enhanced cortical and hippocampal tau pathology, supporting use of these mice for studying Aβ-tau interactions and preclinical screening.

Key findings

  • MAPTP301S;Int10+3;S320F mice showed robust AT8-positive tau pathology before 6 months, strongest in hypothalamus, amygdala, and thalamus with milder cortex and hippocampus involvement; tau accumulation increased age-dependently, with extrapolation suggesting onset at 4–5 months or earlier in hypothalamus.
  • At 6 months, sarkosyl-insoluble phosphorylated tau was detectable, and S1/P3 fractions from hypothalamus and cortex significantly increased seeding activity in tau biosensor cells, comparable to 12-month-old PS19 mice; TOC1-, T22-, and MC1-positive tau was also present.
  • At 12 months, GFAP was upregulated without Iba1 changes; synaptic puncta colocalization was reduced in hypothalamus at 6 months, synaptophysin and synaptotagmin were reduced at 12 months, Gallyas-positive cells appeared in hypothalamus, and MRI showed significant hypothalamus and amygdala volume loss in both mutant lines plus hippocampal volume reduction in MAPTP301S;Int10+3;S320F.
  • In IntelliCage testing of 32 female mice at 9–12 months, MAPTP301S;Int10+3;S320F showed increased same-corner re-entry, more trials to criterion in the CS/PS-shuffled session (group effect F(2, 377) = 7.642, p < 0.001), impaired sustained attention, lower saccharin preference under effort (F(2, 261) = 14.50, p < 0.0001), and increased body weight; AppNL-G-F × MAPTP301S;Int10+3;S320F mice at 6 months had markedly enhanced AT8 positivity in cortex and hippocampus without changes in Aβ plaque density or GFAP/Iba1 versus AppNL-G-F.

Methods

  • Triple-mutant lines were generated by a second round of cytosine base editor editing to introduce S320F into MAPTS305N;Int10+3 and MAPTP301S;Int10+3 mice; off-target candidates were checked by in silico analysis and whole-genome resequencing, and mutants were backcrossed to B6/J mice three or more times to obtain homozygotes.
  • Phenotyping used immunofluorescence/immunohistochemistry with AT8, CP13, PHF-1, TOC1, T22, and MC1; sarkosyl fractionation into S1 and P3 fractions; FRET biosensor seeding assays; GFAP/Iba1 staining; synaptic marker imaging and western blot; Gallyas silver staining; T1 MRI; and IntelliCage behavioral testing.
  • Samples were typically n = 4 per group (2 males and 2 females) at 6, 9, and 12 months; behavior used 32 female mice (MAPT n = 11, MAPTS305N;Int10+3;S320F n = 10, MAPTP301S;Int10+3;S320F n = 11) at 9–12 months, and MRI used n = 5 female mice per group.

Limitations

  • Stated: the triple mutation combination does not occur in real-world human clinical cases, so the model is artificial; the authors also did not examine the protein structure of tau fibrils carrying P301S/S305N and S320F, leaving unknown whether accumulated tau replicates FTD patient tau structure.
  • Evident from the text: pathological onset age was not directly determined and was inferred by extrapolation from AT8 time-course data; the behavioral cohort was female-only, and several biochemical/immunohistochemical analyses used small groups (n = 3–4), limiting sex- and sample-size-based generalization.

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Crossref · 10.1016/j.crmeth.2025.101024

Cites

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Figures

Graphical abstract
Graphical abstract CC BY-NC · PubMed Central
Figure 1 Generation and tau isoform expression patterns of triple-mutant MAPT KI mouse lines (A) Schematic of pathogenic mutations in the human MAPT gene, showing mutations in the exon (left) and intron (right). (B) Workflow of the two genome editing steps for generating MAPTS305N;Int10+3;S320F and MAPTP301S;Int10+3;S320F mice. (C) Four pathogenic mutations introduced by base editing. (D and E) Western blot analysis of alkaline phosphatase-treated tau protein from the frontal cortices of MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at the age of 6 months (D) and densitometric quantification of each isoform (E) (n = 3 per group, 2 males and 1 female). (F and G) RT-PCR analysis of the MAPT gene transcripts from the frontal cortices of MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at the age of 6 months using primer sets specific for 3R tau, 4R tau, and GAPDH (F) and densitometry quantification (G) (n = 4 per group, 2 males and 2 females). (H) Quantitative real-time PCR analysis of the MAPT gene transcripts from the frontal cortices of MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at the age of 6 months (n = 4 per group, 2 males and 2 females). In (E) and (H), the data are presented as mean ± SD (two-way ANOVA with Tukey’s multiple comparison test). ∗∗p < 0.01, ∗∗∗p < 0.005, ∗∗∗∗p < 0.001. n.d., not detected. See also Figures S1 and S2 and Table S2.
Figure 1 Generation and tau isoform expression patterns of triple-mutant MAPT KI mouse lines (A) Schematic of pathogenic mutations in the human MAPT gene, showing mutations in the exon (left) and intron (right). (B) Workflow of the two genome editing steps for generating MAPTS305N;Int10+3;S320F and MAPTP301S;Int10+3;S320F mice. (C) Four pathogenic mutations introduced by base editing. (D and E) Western blot analysis of alkaline phosphatase-treated tau protein from the frontal cortices of MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at the age of 6 months (D) and densitometric quantification of each isoform (E) (n = 3 per group, 2 males and 1 female). (F and G) RT-PCR analysis of the MAPT gene transcripts from the frontal cortices of MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at the age of 6 months using primer sets specific for 3R tau, 4R tau, and GAPDH (F) and densitometry quantification (G) (n = 4 per group, 2 males and 2 females). (H) Quantitative real-time PCR analysis of the MAPT gene transcripts from the frontal cortices of MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at the age of 6 months (n = 4 per group, 2 males and 2 females). In (E) and (H), the data are presented as mean ± SD (two-way ANOVA with Tukey’s multiple comparison test). ∗∗p < 0.01, ∗∗∗p < 0.005, ∗∗∗∗p < 0.001. n.d., not detected. See also Figures S1 and S2 and Table S2.CC BY-NC · PubMed Central
Figure 2 Spatiotemporal mapping of tau pathology in triple-mutant MAPT KI mouse lines (A) Representative coronal sections of 6-month-old MAPTP301S;Int10+3;S320F mice, stained with the AT8 antibody. Scale bar: 500 μm. (B) Schematic of several brain regions used for creating the heatmaps. MO, somatomotor area; SS, somatosensory area; PIR, piriform area; CP, caudoputamen; LS, lateral septal nucleus; HY, hypothalamus; AUD, auditory area; HPF, hippocampal formation; TH, thalamus; AM, amygdala; RSP, retrosplenial area; VIS, visual area; MB, midbrain; ENT, entorhinal area; CB, cerebellum; HB, hindbrain. (C) Heatmaps of AT8 immunopositivity in different brain regions for MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at the age of 6 months. At least four biological replicates (2 males and 2 females) were used for creating the heatmap. (D) Representative AT8 immunostained brain slice images of male MAPTP301S;Int10+3;S320F mice at 6, 9, and 12 months of age. Scale bar: 500 μm. (E) Time curves of AT8 immunopositivity for MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at HY, AM, HPF, and SS (n = 4 per genotype and age, 2 males and 2 females). All immunostaining images were acquired simultaneously under consistent contrast settings. The data are presented as mean ± SD.
Figure 2 Spatiotemporal mapping of tau pathology in triple-mutant MAPT KI mouse lines (A) Representative coronal sections of 6-month-old MAPTP301S;Int10+3;S320F mice, stained with the AT8 antibody. Scale bar: 500 μm. (B) Schematic of several brain regions used for creating the heatmaps. MO, somatomotor area; SS, somatosensory area; PIR, piriform area; CP, caudoputamen; LS, lateral septal nucleus; HY, hypothalamus; AUD, auditory area; HPF, hippocampal formation; TH, thalamus; AM, amygdala; RSP, retrosplenial area; VIS, visual area; MB, midbrain; ENT, entorhinal area; CB, cerebellum; HB, hindbrain. (C) Heatmaps of AT8 immunopositivity in different brain regions for MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at the age of 6 months. At least four biological replicates (2 males and 2 females) were used for creating the heatmap. (D) Representative AT8 immunostained brain slice images of male MAPTP301S;Int10+3;S320F mice at 6, 9, and 12 months of age. Scale bar: 500 μm. (E) Time curves of AT8 immunopositivity for MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at HY, AM, HPF, and SS (n = 4 per genotype and age, 2 males and 2 females). All immunostaining images were acquired simultaneously under consistent contrast settings. The data are presented as mean ± SD.CC BY-NC · PubMed Central
Figure 3 Immunohistochemical analysis of triple-mutant MAPT KI mouse lines (A) Epitope maps of anti-tau antibodies used for this study. (B) Immunohistochemical analysis of HY of male MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at the age of 6 months using CP13, AT8, PHF-1, TOC1, T22, and MC1 antibodies. Scale bars: 50 μm; n = 4 (2 males and 2 females). (C) Colocalization of AT8 signals with MAP2 (a marker for somata and dendrites, top) or KIF5A (a marker for somata and axons, bottom) in the cortical region of 12-month-old MAPTP301S; Int10+3; S320F mice. Scale bars: 5 μm. Pink, white, and red arrows indicate dendrite, soma, and axon, respectively. See also Figure S3.
Figure 3 Immunohistochemical analysis of triple-mutant MAPT KI mouse lines (A) Epitope maps of anti-tau antibodies used for this study. (B) Immunohistochemical analysis of HY of male MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at the age of 6 months using CP13, AT8, PHF-1, TOC1, T22, and MC1 antibodies. Scale bars: 50 μm; n = 4 (2 males and 2 females). (C) Colocalization of AT8 signals with MAP2 (a marker for somata and dendrites, top) or KIF5A (a marker for somata and axons, bottom) in the cortical region of 12-month-old MAPTP301S; Int10+3; S320F mice. Scale bars: 5 μm. Pink, white, and red arrows indicate dendrite, soma, and axon, respectively. See also Figure S3.CC BY-NC · PubMed Central
Figure 4 Sarkosyl fractionation of tau from brain extracts and their seeding potency, analyzed by tau biosensor cells (A) A schematic of sarkosyl fractionation of tau. Sup, supernatant. (B and C) Western blot analyses of TBS-soluble fractions from the TH of MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at the age of 6 months (n = 4 per group, 2 males and 2 females) and PS19 at the age of 6 and 12 months using Tau13, AT8, CP13, and PHF-1 antibodies (B) and densitometry quantification (C). A Mapt knockout mouse was used as a negative control, and PS19 mice were used as positive controls. (D) Western blot analyses of sarkosyl-insoluble fractions from the TH of MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at the age of 6 months using Tau5 and AT8 antibodies (n = 4 per group, 2 males and 2 females). (E) Schematic of the tau seeding assay using tau biosensor cells. (F and G) The percentage of fluorescence resonance energy transfer-positive cells 48 h after incubation with S1 (F) or P3 (G) fractions from the TH of MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at the age of 6 months (n = 4 per group, 2 males and 2 females) and PS19 mice at the age of 6 and 12 months, using biosensor cells.25 In (C), the data are presented as the mean ± SD (two-way ANOVA with Tukey’s multiple comparison test). ∗∗p < 0.01, ∗∗∗p < 0.005, ∗∗∗∗p < 0.001. In (F) and (G), the data are presented as the mean ± SD (one-way ANOVA with Tukey’s multiple comparison test). ∗∗∗∗p < 0.001. See also Figure S4.
Figure 4 Sarkosyl fractionation of tau from brain extracts and their seeding potency, analyzed by tau biosensor cells (A) A schematic of sarkosyl fractionation of tau. Sup, supernatant. (B and C) Western blot analyses of TBS-soluble fractions from the TH of MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at the age of 6 months (n = 4 per group, 2 males and 2 females) and PS19 at the age of 6 and 12 months using Tau13, AT8, CP13, and PHF-1 antibodies (B) and densitometry quantification (C). A Mapt knockout mouse was used as a negative control, and PS19 mice were used as positive controls. (D) Western blot analyses of sarkosyl-insoluble fractions from the TH of MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at the age of 6 months using Tau5 and AT8 antibodies (n = 4 per group, 2 males and 2 females). (E) Schematic of the tau seeding assay using tau biosensor cells. (F and G) The percentage of fluorescence resonance energy transfer-positive cells 48 h after incubation with S1 (F) or P3 (G) fractions from the TH of MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at the age of 6 months (n = 4 per group, 2 males and 2 females) and PS19 mice at the age of 6 and 12 months, using biosensor cells.25 In (C), the data are presented as the mean ± SD (two-way ANOVA with Tukey’s multiple comparison test). ∗∗p < 0.01, ∗∗∗p < 0.005, ∗∗∗∗p < 0.001. In (F) and (G), the data are presented as the mean ± SD (one-way ANOVA with Tukey’s multiple comparison test). ∗∗∗∗p < 0.001. See also Figure S4.CC BY-NC · PubMed Central
Figure 5 Neuroinflammation, synaptic loss, and neurodegeneration in triple-mutant MAPT KI mice (A–C) GFAP and Iba1 immunohistochemistry to assess neuroinflammation (A) and quantification of immuno-positive signals in the HY of 12-month-old MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice (n = 4 per group, 2 males and 2 females). Scale bars: 50 μm (B and C). (D and E) Representative super-resolution images of synaptotagmin and Homer1 punctum colocalization in the HY of 6-month-old MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F lines (D) and quantification of synaptotagmin/Homer1 colocalization density in the HY of 6-month-old MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice (n = 4 per group, 2 males and 2 females) (E). White arrows indicate colocalized signals. (F) Immunoblotting of synaptic markers detected by anti-synaptophysin, synaptotagmin, PSD95, and β-actin antibodies in the Tris-soluble fraction of brain lysates from MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at 12 months of age (n = 4 per group, 2 males and 2 females). (G) Gallyas silver staining in the HY of MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice and in the AM of PS19 mice at 12 months of age as a positive control. Scale bars: 50 μm. (H and I) Regional analysis of T1 MRI images obtained from MAPT, MAPTS305N;Int10+3;S320F and MAPTP301S;Int10+3;S320F mice at the age of 12 months (n = 5 per group, female). Scale bars: 1 mm. In (B) and (E), the data are presented as the mean ± SD (one-way ANOVA with Tukey’s multiple comparison test). ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.005. In (F) and (I), the data are presented as the mean ± SD (two-way ANOVA with Tukey’s multiple comparison test). ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.005, ∗∗∗∗p < 0.001. See also Figure S5 and S6.
Figure 5 Neuroinflammation, synaptic loss, and neurodegeneration in triple-mutant MAPT KI mice (A–C) GFAP and Iba1 immunohistochemistry to assess neuroinflammation (A) and quantification of immuno-positive signals in the HY of 12-month-old MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice (n = 4 per group, 2 males and 2 females). Scale bars: 50 μm (B and C). (D and E) Representative super-resolution images of synaptotagmin and Homer1 punctum colocalization in the HY of 6-month-old MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F lines (D) and quantification of synaptotagmin/Homer1 colocalization density in the HY of 6-month-old MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice (n = 4 per group, 2 males and 2 females) (E). White arrows indicate colocalized signals. (F) Immunoblotting of synaptic markers detected by anti-synaptophysin, synaptotagmin, PSD95, and β-actin antibodies in the Tris-soluble fraction of brain lysates from MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice at 12 months of age (n = 4 per group, 2 males and 2 females). (G) Gallyas silver staining in the HY of MAPT, MAPTS305N;Int10+3;S320F, and MAPTP301S;Int10+3;S320F mice and in the AM of PS19 mice at 12 months of age as a positive control. Scale bars: 50 μm. (H and I) Regional analysis of T1 MRI images obtained from MAPT, MAPTS305N;Int10+3;S320F and MAPTP301S;Int10+3;S320F mice at the age of 12 months (n = 5 per group, female). Scale bars: 1 mm. In (B) and (E), the data are presented as the mean ± SD (one-way ANOVA with Tukey’s multiple comparison test). ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.005. In (F) and (I), the data are presented as the mean ± SD (two-way ANOVA with Tukey’s multiple comparison test). ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.005, ∗∗∗∗p < 0.001. See also Figure S5 and S6.CC BY-NC · PubMed Central
Figure 6 Behavioral abnormalities in triple-mutant MAPT KI mouse lines using the IntelliCage system (A) Overview of the IntelliCage. Two IntelliCages were used to test a total of 32 female mice: MAPT (n = 11), MAPTS305N;Int10+3;S320F (n = 10), and MAPTP301S;Int10+3;S320F (n = 11); 5 or 6 mice per genotype per IntelliCage. The mice were assessed at ages ranging from 9 to 12 months, as this experiment lasted for 3 months. (B) Activity in a novel environment. Hourly cumulative number of corner visits, nosepokes, and licking bouts during the first 24 h after the mice were introduced to the IntelliCage. (C) Basal activity represented as daily averages over a 14-day period. (D) Frequency of re-entries to the same corner in all patterns of corner-to-corner movements. (E) Learning and behavioral flexibility assessment. Shown is the number of trials to reach criterion required for completing each phase of the CS-only session (top) and the CS/PS-shuffled session (bottom). (F) Behavioral inhibition and sustained attention test. Mice were required to withhold nosepokes during the delay time (DT). Nosepokes during the DT were recorded as premature responses. The response time between the second LED-on signal and the subsequent nosepoke was used as a measure of sustained attention. (G) Sweet taste preference test and effort-based choice test. In both tests, one side of the nosepoke hole in each corner led to saccharin water, while the other side led to plain water. For the sweet taste preference test, the percentage of saccharin choice over 2 days is plotted. For the effort-based choice test, the percentage of saccharin choice is plotted against the number of nosepokes required to obtain saccharin water. (H) Summary of behavioral test results observed in mutant lines from the IntelliCage experiments. The data are presented as the mean ± SD. Statistical significance was examined by two-way/one-way ANOVA (B–G) and Tukey’s multiple comparisons test. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.005, ∗∗∗∗p < 0.001. See also Figure S7.
Figure 6 Behavioral abnormalities in triple-mutant MAPT KI mouse lines using the IntelliCage system (A) Overview of the IntelliCage. Two IntelliCages were used to test a total of 32 female mice: MAPT (n = 11), MAPTS305N;Int10+3;S320F (n = 10), and MAPTP301S;Int10+3;S320F (n = 11); 5 or 6 mice per genotype per IntelliCage. The mice were assessed at ages ranging from 9 to 12 months, as this experiment lasted for 3 months. (B) Activity in a novel environment. Hourly cumulative number of corner visits, nosepokes, and licking bouts during the first 24 h after the mice were introduced to the IntelliCage. (C) Basal activity represented as daily averages over a 14-day period. (D) Frequency of re-entries to the same corner in all patterns of corner-to-corner movements. (E) Learning and behavioral flexibility assessment. Shown is the number of trials to reach criterion required for completing each phase of the CS-only session (top) and the CS/PS-shuffled session (bottom). (F) Behavioral inhibition and sustained attention test. Mice were required to withhold nosepokes during the delay time (DT). Nosepokes during the DT were recorded as premature responses. The response time between the second LED-on signal and the subsequent nosepoke was used as a measure of sustained attention. (G) Sweet taste preference test and effort-based choice test. In both tests, one side of the nosepoke hole in each corner led to saccharin water, while the other side led to plain water. For the sweet taste preference test, the percentage of saccharin choice over 2 days is plotted. For the effort-based choice test, the percentage of saccharin choice is plotted against the number of nosepokes required to obtain saccharin water. (H) Summary of behavioral test results observed in mutant lines from the IntelliCage experiments. The data are presented as the mean ± SD. Statistical significance was examined by two-way/one-way ANOVA (B–G) and Tukey’s multiple comparisons test. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.005, ∗∗∗∗p < 0.001. See also Figure S7.CC BY-NC · PubMed Central
Figure 7 Effects of Aβ deposition on tau pathology in the hippocampus and cortex of MAPTP301S;Int10+3;S320F mice (A and B) Representative AT8 immunostaining images of brain sections from MAPTP301S;Int10+3;S320F and AppNL-G-F × MAPTP301S;Int10+3;S320F mice at the age of 6 months (A) and their quantification in cortex, hippocampus, HY, and AM regions (n = 3 per group, 2 males and 1 female) (B). Scale bars: 500 μm and 100 μm (insets). (C and D) Representative Aβ immunostaining images of brain sections from AppNL-G-F and AppNL-G-F × MAPTP301S;Int10+3;S320F mice at the age of 6 months (C) and their quantification in cortex, hippocampus, HY, and AM regions (n = 4 per group, 2 males and 2 females) (D). Scale bars: 500 μm and 100 μm (insets). (E–G) Immunostaining of GFAP and Iba1 in the brain sections from AppNL-G-F and AppNL-G-F × MAPTP301S;Int10+3;S320F mice at the age of 6 months (E) and regional quantification of positive area of GFAP (F) and Iba1 (G) (n = 4 per group, 2 males and 2 females). In (B), the data are presented as the mean ± SD (two-way ANOVA with Tukey’s multiple comparison test). ∗p < 0.05, ∗∗p < 0.01.
Figure 7 Effects of Aβ deposition on tau pathology in the hippocampus and cortex of MAPTP301S;Int10+3;S320F mice (A and B) Representative AT8 immunostaining images of brain sections from MAPTP301S;Int10+3;S320F and AppNL-G-F × MAPTP301S;Int10+3;S320F mice at the age of 6 months (A) and their quantification in cortex, hippocampus, HY, and AM regions (n = 3 per group, 2 males and 1 female) (B). Scale bars: 500 μm and 100 μm (insets). (C and D) Representative Aβ immunostaining images of brain sections from AppNL-G-F and AppNL-G-F × MAPTP301S;Int10+3;S320F mice at the age of 6 months (C) and their quantification in cortex, hippocampus, HY, and AM regions (n = 4 per group, 2 males and 2 females) (D). Scale bars: 500 μm and 100 μm (insets). (E–G) Immunostaining of GFAP and Iba1 in the brain sections from AppNL-G-F and AppNL-G-F × MAPTP301S;Int10+3;S320F mice at the age of 6 months (E) and regional quantification of positive area of GFAP (F) and Iba1 (G) (n = 4 per group, 2 males and 2 females). In (B), the data are presented as the mean ± SD (two-way ANOVA with Tukey’s multiple comparison test). ∗p < 0.05, ∗∗p < 0.01.CC BY-NC · PubMed Central

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Authors
Morito, T., Qi, M., Kamano, N., Sasaguri, H., Bez, S., Foiani, M., Duff, K., Benner, S., Endo, T., Hama, H., Kurokawa, H., Miyawaki, A., Mizuma, H., Sahara, N., Shimojo, M., Higuchi, M., Saido, T. C., & Watamura, N.
Affiliations
  • RIKEN Center for Brain Science (JP)
  • UK Dementia Research Institute (GB)
  • National Institute for Environmental Studies (JP)
  • Japan Chemical Analysis Center (JP)
  • National Institutes for Quantum Science and Technology (JP)
Corresponding author
  • Saido, Takaomi C.
  • Watamura, Naoto
ORCID
Venue
Cell Reports Methods
Publisher
Elsevier BV
Published
2025-04
Volume
5
Issue
4
Pages
101024
ISSN
2667-2375 (ISSN-L)
DOI
10.1016/j.crmeth.2025.101024
PMC
PMC12256944
OpenAlex
W4409348394
Cited by
18
References
93
Citations by year
2026: 11 · 2025: 6
FWCI
4.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports Methods (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (submittedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
  • QST-Repository (National Institutes for Quantum and Radiological Science and Technology) (submittedVersion)
Funders
  • JSPS (24K18633)
  • Japan Agency for Medical Research and Development (JP20dm0207001)
  • Japan Society for the Promotion of Science (23K26790, 21K15378)
  • UK Dementia Research Institute
  • Uehara Memorial Foundation
  • RIKEN
  • Cell Science Research Foundation
  • Alzheimer's Association
  • Medical Research Council
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
frontotemporal dementia, tauopathy, tau pathology, amyloid-beta, thalamus, hypothalamus, amygdala, synaptic loss, brain atrophy, behavioral abnormalities, in vivo drug screening
MeSH terms
Animals, Brain, Disease Models, Animal, Humans, Mice, Transgenic, Mutation, tau Proteins, Mice, Gene Knock-In Techniques, Frontotemporal Dementia

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-11-13, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-13 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Human MAPT knockin mouse models of frontotemporal dementia for the neurodegenerative research community. https://app.cochat.ai/papers/10.1016/j.crmeth.2025.101024
The paper
Morito, T., Qi, M., Kamano, N., Sasaguri, H., Bez, S., Foiani, M., Duff, K., Benner, S., Endo, T., Hama, H., Kurokawa, H., Miyawaki, A., Mizuma, H., Sahara, N., Shimojo, M., Higuchi, M., Saido, T. C., & Watamura, N. (2025). Human MAPT knockin mouse models of frontotemporal dementia for the neurodegenerative research community. Cell Reports Methods. https://doi.org/10.1016/j.crmeth.2025.101024

Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.