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Cited by 18Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Characterization of a Mouse Model of Alzheimer’s Disease Expressing Aβ4-42 and Human Mutant Tau

Open access
Zampar, Silvia, Wirths, Oliver·2021·International Journal of Molecular Sciences
DOI 10.3390/ijms22105191PMC PMC8156793
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Abstract

The relationship between the two most prominent neuropathological hallmarks of Alzheimer’s Disease (AD), extracellular amyloid-β (Aβ) deposits and intracellular accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFT), remains at present not fully understood. A large body of evidence places Aβ upstream in the cascade of pathological events, triggering NFTs formation and the subsequent neuron loss. Extracellular Aβ deposits were indeed causative of an increased tau phosphorylation and accumulation in several transgenic models but the contribution of soluble Aβ peptides is still controversial. Among the different Aβ variants, the N-terminally truncated peptide Aβ4–42 is among the most abundant. To understand whether soluble Aβ4–42 peptides impact the onset or extent of tau pathology, we have crossed the homozygous Tg4–42 mouse model of AD, exclusively expressing Aβ4–42 peptides, with the PS19 (P301S) tau transgenic model. Behavioral assessment showed that the resulting double-transgenic line presented a partial worsening of motor performance and spatial memory deficits in the aged group. While an increased loss of distal CA1 pyramidal neurons was detected in young mice, no significant alterations in hippocampal tau phosphorylation were observed in immunohistochemical analyses.

AI snapshot

Written from the paper’s full text.

TL;DR

Crossing Aβ4–42-expressing Tg4–42 mice with P301S tau PS19 mice produced a double-transgenic line with partial motor and spatial memory worsening and early distal CA1 neuron loss, but no clear aggravation of hippocampal tau phosphorylation. The authors conclude that soluble Aβ4–42 alone may not accelerate NFT formation in the way models with extracellular amyloid plaques do.

Key findings

  • PS19/Tg4–42hom mice showed partial motor worsening: at 3 months, Tg4–42hom and PS19/Tg4–42hom had reduced rotarod fall latencies vs WT (p < 0.05) and PS19 (p < 0.001); at 5 months, PS19/Tg4–42hom showed reduced balance-beam latency vs WT, PS19, and Tg4–42hom (p < 0.001).
  • Spatial memory deficits emerged in bigenic mice: at 5 months, PS19/Tg4–42hom lacked goal-quadrant preference in the MWM probe trial, and at 9 months all transgenic lines spent less time in the target quadrant than WT; PS19/Tg4–42hom performed worst among transgenic lines.
  • PS19/Tg4–42hom had increased distal CA1 neuron loss vs Tg4–42hom at 3 months (p < 0.01), but no difference in distal or proximal CA1 at 5 or 9 months. Tg4–42hom showed ~20%, ~40%, and ~45% total CA1 neuron loss vs WT at 3, 5, and 9 months.
  • No significant difference in hippocampal Aβ load was detected between Tg4–42hom and PS19/Tg4–42hom at 3, 5, or 9 months. AT8 phospho-tau showed only a trend toward increase at 3 months (p = 0.0573), no significant difference at 5 months, and no significant difference at 9 months despite abundant NFTs in both PS19 and bigenic mice.

Methods

  • Bigenic PS19/Tg4–42hom mice were generated by crossing homozygous Tg4–42 mice, expressing Aβ4–42 under the Thy1 promoter, with PS19 mice expressing human P301S mutant tau; mice were maintained on a C57BL/6J background, with equal numbers of female and male transgenic and WT mice at 3, 5, and 9 months.
  • Behavioral testing included accelerating rotarod, balance beam, inverted grid, Morris water maze, and novel object recognition. Transgene mRNA expression was measured by qRT-PCR.
  • Neuropathology used hematoxylin staining for CA1 neuron counts and immunohistochemistry with 24311 (pan-Aβ) and AT8 (phospho-tau pSer202/pThr205) antibodies, quantified in ImageJ. Statistical analyses used Shapiro–Wilk normality testing, t-tests, one-way or repeated-measures two-way ANOVA with Bonferroni post hoc, and Mann–Whitney tests where non-parametric.

Limitations

  • The paper states that the lack of a 5-month neuron-loss difference between bigenic and Tg4–42hom mice may reflect the already profound CA1 neuron loss and plateau in single Tg4–42hom mice; it also notes that aged behavioral deficits in the bigenic line could not be related to aggravated neuron loss or tau pathology.
  • The authors state that Tg4–42 mice do not form overt extracellular Aβ plaques, so the model cannot directly test whether plaque pathology is required for enhanced NFT formation; they conclude that extracellular amyloid plaques might be a prerequisite for accelerated tau aggregation in APP/tau transgenic models.
  • Evident from the text: immunohistochemical tau analyses used limited sample sizes (n = 5–6 per time point) and neuron counts used n = 6–7 per time point, with three sections per animal; the study also relies on a single tau transgenic model and does not report protein-level validation of transgene expression.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/ijms22105191

Cites

50 of 50 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

29 of 54 cited sources checked · 17 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Tg4-42 mice overexpress Aβ4-42 peptides under the control of the murine neuron-specific Thy1 promoter.

    “We have recently generated a transgenic mouse model (Tg4–42) that overexpresses Aβ4–42 peptides under the control of the murine neuron-specific Thy1-promoter [21].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [21] Bouter, 2013, N-truncated amyloid β (Aβ) 4–42 forms stable aggregates and induces acute and long-lasting behavioral deficits, Acta Neuropathol. source
  • Premisecitation

    Aβ4-42 is predominantly expressed in the CA1 region in Tg4-42hom mice.

    “As Aβ4–42 is predominantly expressed in the CA1 region in Tg4–42hom mice [21], hippocampal mRNA extracts were used for the analysis of both transgenes.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [21] Bouter, 2013, N-truncated amyloid β (Aβ) 4–42 forms stable aggregates and induces acute and long-lasting behavioral deficits, Acta Neuropathol. source

      The Results section ('Aβ4-42 expression in Tg4-42 mice,' Fig. 4) reports predominantly CA1 immunoreactivity, but the staining shown is from hemizygous mice. The paper reports CA1 neuron loss in homozygous mice (Results, Fig. 5), not a separate finding that Aβ4-42 expression is predominantly CA1 in those mice. Page numbers were not available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation

    Tg4-42 mice do not form overt extracellular Aβ deposits.

    “Tg4–42 mice do not form overt extracellular Aβ deposits but present robust behavioral deficits together with abundant CA1 neuron loss at an age of 6 months [24,25].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [24] Brauss, 2016, Physical activity delays hippocampal neurodegeneration and rescues memory deficits in an Alzheimer disease mouse model, Transl. Psych. source
    • cites [25] Stazi, 2021, Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzheimer’s Disease, Mol. Neurobiol. source
  • Findingcitation

    Tg4-42hom mice presented expected age-dependent neuron loss with total CA1 neuron loss of approximately 20%, 40% and 45% compared to WT mice at 3, 5 and 9 months, respectively.

    “Tg4–42hom mice presented the expected age-dependent neuron loss with a total CA1 (calculated as distal + proximal) neuron loss of approximately 20%, 40% and 45% compared to WT mice at 3, 5 and 9 months, respectively (Supplementary Figure S6), confirming previous data obtained with stereological analyses [27].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [27] Antonios, 2015, Alzheimer therapy with an antibody against N-terminal Abeta 4-X and pyroglutamate Abeta 3-X, Sci. Rep. source
  • Interpretationcitation

    Findings in models harboring transgenic Aβ peptides in the absence of APP overexpression strikingly contrast the obvious exacerbation of tau pathology observed in tau transgenic mice when crossed with mouse models of AD overexpressing mutant APP.

    “These findings in models harboring transgenic Aβ peptides in the absence of APP overexpression strikingly contrast the obvious exacerbation of tau pathology observed in tau transgenic mice when crossed with mouse models of AD overexpressing mutant APP [7,8,9,10,11,12,13,36].”
    Quote in the paperSubstantial claim3 of 8 sources checked
    • cites [7] Grueninger, 2010, Phosphorylation of Tau at S422 is enhanced by Abeta in TauPS2APP triple transgenic mice, Neurobiol. Dis. source
    • cites [8] Hurtado, 2010, Aβ accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model, Am. J. Pathol. source
    • cites [9] Saul, 2013, Accelerated tau pathology with synaptic and neuronal loss in a novel triple transgenic mouse model of Alzheimer’s disease, Neurobiol. Aging source
    • cites [10] Stancu, 2014, Tauopathy contributes to synaptic and cognitive deficits in a murine model for Alzheimer’s disease, FASEB J. source
    • cites [11] Lewis, 2001, Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP, Science source
    • cites [12] Kang, 2021, Spatial memory deficiency early in 6xTg Alzheimer’s disease mouse model, Sci. Rep. source
    • cites [13] Goufak, 2014, Increased misfolding and truncation of tau in APP/PS1/tau transgenic mice compared to mutant tau mice, Neurobiol. Dis. source
    • cites [36] Chabrier, 2012, Soluble abeta promotes wild-type tau pathology in vivo, J. Neurosci. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 22
  • May combine two claims. 36

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Using the same line of P301S tau transgenic mice, a trend towards a higher extracellular amyloid plaque load was detected in PDAPP/Tau bigenic mice.

    “Using the same line of P301S tau transgenic mice, a trend towards a higher extracellular amyloid plaque load was detected in PDAPP/Tau bigenic mice [8], while no evidence for increased Aβ pathology was evident in 5XFAD/PS19 mice at either 3 or 9 months of age [9].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [8] Hurtado, 2010, Aβ accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model, Am. J. Pathol. source

      The Discussion states the opposite trend: bigenic PS19;PDAPP mice had fewer Aβ deposits, not a higher plaque load. Figure 6 likewise describes greater plaque burden in monogenic PDAPP mice. (LLM, conf=0.94)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Homozygous Tg4-42 mice display age-dependent neuron loss in the CA1 region of the hippocampus, reaching a plateau after 6 months of age, a time point when deficits become evident in a variety of behavioral tasks.

    “Homozygous Tg4–42 mice display an age-dependent neuron loss in the CA1 region of the hippocampus, reaching a plateau after 6 months of age, a time point when deficits become evident in a variety of behavioral tasks [27].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [27] Antonios, 2015, Alzheimer therapy with an antibody against N-terminal Abeta 4-X and pyroglutamate Abeta 3-X, Sci. Rep. source

      The Results section on CA1 neuron loss reports age-dependent loss in homozygous Tg4-42 mice, but it rises from 50% at six months to 64% at eight months, contrary to a plateau after six months. The Results section on spatial reference memory reports clear deficits by six months in the Morris water maze, but does not establish deficits across a variety of behavioral tasks. Page numbers are unavailable in our copy. (LLM, conf=0.91)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Tg4-42 mice present robust behavioral deficits and abundant CA1 neuron loss at 6 months of age.

    “Tg4–42 mice do not form overt extracellular Aβ deposits but present robust behavioral deficits together with abundant CA1 neuron loss at an age of 6 months [24,25].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [24] Brauss, 2016, Physical activity delays hippocampal neurodegeneration and rescues memory deficits in an Alzheimer disease mouse model, Transl. Psych. source
    • cites [25] Stazi, 2021, Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzheimer’s Disease, Mol. Neurobiol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Aβ4-42 is among the most abundant N-terminally truncated Aβ peptides.

    “Among the different Aβ variants, the N-terminally truncated peptide Aβ4–42 is among the most abundant.”
    • Also stated in: § 1. Introduction · plain
      “Aβ4–42 peptides are among the first Aβ peptides that have been identified in human AD brain and represent a highly abundant peptide species [1,22,23].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [1] Masters, 1985, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proc. Natl. Acad. Sci. USA source
    • cites [22] Portelius, 2010, Mass spectrometric characterization of brain amyloid beta isoform signatures in familial and sporadic Alzheimer’s disease, Acta Neuropathol. source
    • cites [23] Wirths, 2019, Emerging roles of N- and C-terminally truncated Aβ species in Alzheimer’s disease, Expert Opin. Ther. Targets source

  • May combine two claims.

    Interpretationcitation

    The slightly better rotarod performance of PS19 mice is consistent with a hyperactivity phenotype in 6-month-old PS19 mice, presenting better albeit not statistically significant performance on the rotarod compared to WT control animals.

    “This is consistent with a hyperactivity phenotype in 6-month-old PS19 mice, presenting with better, albeit not statistically significant, performance on the rotarod compared to WT control animals [28].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] Takeuchi, H., Iba, M., Inoue, H., Higuchi, M., Takao, K., Tsukita, K., Karatsu, Y., Iwamoto, Y., Miyakawa, T., and Suhara, T. (2011). P301S Mutant Human Tau Transgenic Mice Manifest Early Symptoms of Human Tauopathies with Dementia and Altered Sensorimotor Gating. PLoS ONE, 6. source

      The Results section ('Locomotor activity and motor coordination'; page unavailable) reports no statistically significant rotarod difference from wild-type mice, and the Results section on hyperactivity reports that the mutant mice were more hyperactive. However, Materials and Methods ('Rotarod test'; page unavailable) specifies 15-week-old mice, not 6-month-old mice, and the text does not report better rotarod performance in the mutants. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An induction of tau pathology was observed in P301L tau transgenic mice after infusion of an Aβ-containing brain extract from a 24-month-old APP23 mouse.

    “A substantially increased number of NFTs was detected in P301L tau transgenic mice following injection of fibrillary Aβ42 peptides [30] and an induction of tau pathology was observed in the same line of tau transgenic mice after infusion of an Aβ-containing brain extract from a 24-month-old APP23 mouse [31].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [31] Bolmont, 2007, Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice, Am. J. Pathol. source

  • May combine two claims.

    Interpretationcitation

    At 5 months, bigenic mice showed spatial memory deficits in the MWM task, however neuron numbers did not differ significantly from single transgenic Tg4-42hom mice still learning the task, confirming results from a previous study employing 5-month-old Tg4-42hom mice.

    “At this time point, bigenic mice showed spatial memory deficits in the MWM task, however, it has to be noted that neuron numbers did not differ significantly from single transgenic Tg4–42hom mice still learning the task, confirming results from a previous study employing 5-month-old Tg4–42hom mice [27].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [27] Antonios, 2015, Alzheimer therapy with an antibody against N-terminal Abeta 4-X and pyroglutamate Abeta 3-X, Sci. Rep. source

  • May combine two claims.

    Premisecitation

    The Tg4-42 mouse model used in the present study primarily shows an intraneuronal accumulation of Aβ peptides, in particular in CA1 hippocampal neurons, and does not form overt extracellular plaques.

    “The Tg4–42 mouse model used in the present study primarily shows an intraneuronal accumulation of Aβ peptides, in particular in CA1 hippocampal neurons, and does not form overt extracellular plaques [21].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [21] Bouter, 2013, N-truncated amyloid β (Aβ) 4–42 forms stable aggregates and induces acute and long-lasting behavioral deficits, Acta Neuropathol. source

      The Results section (“Aβ4-42 expression in Tg4-42 mice,” Fig. 4d) reports abundant intraneuronal Aβ immunoreactivity in CA1 hippocampal neurons and says staining was predominantly in CA1. The passages do not establish that Tg4-42 mice lack overt extracellular plaques; a search for extracellular plaques and deposits found no such statement. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The distal part of the CA1 region appears to be mainly involved in non-spatial memory, while the proximal part is supposed to play a more important role in tasks depending on spatial information.

    “While the distal part of the CA1 region appears to be mainly involved in non-spatial memory, the proximal part is supposed to play a more important role in tasks depending on spatial information [39,40].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [39] Masurkar, 2018, Towards a circuit-level understanding of hippocampal CA1 dysfunction in Alzheimer’s disease across anatomical axes, J. Alzheimer’s Dis. Park. source
    • cites [40] Beer, Z., Vavra, P., Atucha, E., Rentzing, K., Heinze, H.-J., and Sauvage, M.M. (2018). The memory for time and space differentially engages the proximal and distal parts of the hippocampal subfields CA1 and CA3. PLoS Biol., 16. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recent data suggested that the toxic effects of oligomeric tau on memory and long-term potentiation (LTP) in WT mice appear to be APP-dependent.

    “In addition, recent data suggested that the toxic effects of oligomeric tau on memory and long-term potentiation (LTP) in WT mice appear to be APP-dependent [38].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [38] Puzzo, 2017, LTP and memory impairment caused by extracellular Aβ and Tau oligomers is APP-dependent, eLife source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The presence of spatial memory deficits in the PS19 line is controversial, with some studies pointing towards deficits in the MWM test from 5 or 6.5 months, while others report initial deficits in spatial memory at 10 or 12 months of age.

    “The presence of spatial memory deficits in the PS19 line is controversial, with some studies pointing towards the development of deficits in the MWM test from a relatively young age of 5 [28] or 6.5 months [41], while others report initial deficits in spatial memory at 10 [42] or even 12 months of age [29], respectively.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [28] Takeuchi, H., Iba, M., Inoue, H., Higuchi, M., Takao, K., Tsukita, K., Karatsu, Y., Iwamoto, Y., Miyakawa, T., and Suhara, T. (2011). P301S Mutant Human Tau Transgenic Mice Manifest Early Symptoms of Human Tauopathies with Dementia and Altered Sensorimotor Gating. PLoS ONE, 6. source

      The Results (Spatial learning abilities; page unavailable) report impaired Morris water maze performance in the transgenic mice. Materials and Methods (Experimental design; page unavailable) specifies that the water-maze mice were six months old, not exactly five or 6.5 months old. The study supports an early spatial-memory deficit, but a single age of testing does not establish when deficits first appeared. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [41] Eckenweber, 2020, Longitudinal TSPO expression in tau transgenic P301S mice predicts increased tau accumulation and deteriorated spatial learning, J. Neuroinflamm. source

      The Results (no page available) report Morris water maze deficits in P301S mice at 6.3 months, supporting the early-deficit part of the cited clause. However, Animals and study design identifies these mice as a human P301S tau line driven by the murine thy1 promoter; our copy does not identify them as the PS19 line. The test age is also 6.3, rather than 6.5, months. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [42] Chalermpalanupap, 2018, Locus Coeruleus Ablation Exacerbates Cognitive Deficits, Neuropathology, and Lethality in P301S Tau Transgenic Mice, J. Neurosci. source

      The Morris water maze Results (page unavailable) show that unlesioned P301S mice learned at 4 and 6 months but did not show significant learning at 10 months, supporting the age attributed to this source. The same section reports that only P301S mice with LC lesions showed a significant probe-trial memory deficit at 10 months; it does not establish a spatial memory-recall deficit in the unlesioned PS19 line at that age. The 5-, 6.5-, and 12-month findings are attached to other citations in the citing sentence. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Pre-aggregated Aβ is able to induce fibrillization of tau both in vitro and in vivo.

    “Related findings were reported by Vasconselos and colleagues, showing that pre-aggregated Aβ is able to induce fibrillization of tau both in vitro and in vivo [32], and interestingly, passive immunization against Aβ in the 3xTg mouse model not only reduced extracellular amyloid plaques but also resulted in decreased tau pathology [33].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] Vasconcelos, 2016, Heterotypic seeding of Tau fibrillization by pre-aggregated Abeta provides potent seeds for prion-like seeding and propagation of Tau-pathology in vivo, Acta Neuropathol. source

      The Results section on the cell-free assay reports that pre-aggregated Aβ directly seeded tau fibrillization in vitro. The in vivo Results instead report fibrillary tau pathology after injection of Aβ-seeded tau aggregates into transgenic mice; they do not establish that pre-aggregated Aβ itself induced tau fibrillization in vivo. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A related observation was reported recently in 3.5- to 12-month-old PS19 mice, showing a ~10% prolonged latency in the accelerating rotarod test.

    “A related observation was reported recently in 3.5- to 12-month-old PS19 mice, showing a ~10% prolonged latency in the accelerating rotarod test [29].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [29] Sun, 2020, The behavioural and neuropathologic sexual dimorphism and absence of MIP-3α in tau P301S mouse model of Alzheimer’s disease, J. Neuroinflamm. source

      The Results section ('P301S mice exhibited sex differences in coordination score system'; page unavailable) reports a 10% longer accelerating-rotarod fall latency in P301S transgenic mice than in wild-type mice. The Mice and Accelerating rotarod methods sections identify the PS19 line and describe monthly behavioral testing from 3 to 12 months, not the claimed 3.5-to-12-month age range. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Recognition performance was quantified using the Discrimination Index (DI).

    “The recognition performances was quantified using the Discrimination Index (DI), measured as the differences between novel (Tnovel) and familiar (Tfamiliar) object exploration times in proportion to the animal’s total exploration time (Ttotal) [25].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Stazi, 2021, Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzheimer’s Disease, Mol. Neurobiol. source

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Neuron loss was assessed in the CA1 region of the hippocampus on sagittal brain sections as previously described.

    “Neuron loss was assessed in the CA1 region of the hippocampus on sagittal brain sections (bregma 0.72–1.08) of 3- and 5-month-old mice (n = 6–7 per time point) as previously described [25].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [25] Stazi, 2021, Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzheimer’s Disease, Mol. Neurobiol. source

  • May combine two claims.

    Findingown data

    Direct comparison of time spent in the goal quadrant during the probe trial revealed a significant reduction in PS19/Tg4-42hom compared to WT (p < 0.001) and Tg4-42hom (p < 0.05) mice, starting at 3 months and persisting at 5 months, while no differences were observed compared to PS19 littermates.

    “A direct comparison of time spent in the goal quadrant during the probe trial among the groups revealed a significant reduction in PS19/Tg4–42hom compared to WT (p < 0.001) and Tg4–42hom (p < 0.05) mice, starting already at 3 months of age and persisting at 5 months, while no differences were observed compared to PS19 littermates (Supplementary Figure S3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PS19/Tg4-42hom mice showed significantly fewer entries into the platform zone at 5 months but not at 3 months.

    “Additionally, PS19/Tg4–42hom mice showed significantly less entries into the platform zone at 5 (Figure 3k) but not at 3 months (Figure 3j) and spent significantly less time in the platform zone during the probe trial compared to the WT group, both at 3 and 5 months (p < 0.05 and p < 0.01, respectively) (Figure 3m,n).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Though PS19/Tg4-42hom mice showed the lowest DI of all groups at the 5-month time point, they did not perform significantly worse compared to the other genotypes.

    “Though PS19/Tg4–42hom mice showed the lowest DI of all groups at the 5-month time point, they did not perform significantly worse compared to the other genotypes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Deficits in PS19/Tg4-42hom mice worsened over time, with poorer performance at 5 months in acquisition training and significantly increased latency to reach the platform compared to all other investigated lines (p < 0.001).

    “The deficits observed in PS19/Tg4–42hom mice worsened over time, with a poorer performance at 5 months in the acquisition training and a significantly increased latency to reach the platform compared to all other investigated lines (p < 0.001) (Figure 3b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aged Tg4-42hom and PS19/Tg4-42hom mice showed significantly reduced fall latency in the balance beam compared to WT and PS19 animals, with no differences between the two impaired lines.

    “Aged Tg4–42hom, in addition to PS19/Tg4–42hom mice, showed a significantly reduced fall latency compared to WT and PS19 animals (Figure 2f), though no differences were observed between the two impaired lines.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the aged group, both PS19 and PS19/Tg4-42hom mice had significantly reduced body weight compared to WT mice (p < 0.05 for PS19, p < 0.001 for PS19/Tg4-42hom).

    “In the aged group, both PS19 and PS19/Tg4–42hom mice revealed a significantly reduced body weight compared to WT mice (p < 0.05 for PS19, p < 0.001 for PS19/Tg4–42hom) (Figure 1i).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At 9 months, Tg4-42hom and PS19/Tg4-42hom lines showed reduced average speed in cue training, but no differences were observed in the acquisition training session.

    “While the WT group was the one usually swimming most slowly at 3 and 5 months, at 9 months, Tg4–42hom and PS19/Tg4–42hom lines showed a reduced average speed in the cue training, but no differences were observed in the acquisition training session (Supplementary Figure S2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At 5 months, rotarod deficits remained consistent but significant differences were found only in comparison to the PS19 line (p < 0.05 for PS19/Tg4-42hom, p < 0.001 for Tg4-42hom).

    “At 5 months, these deficits remained consistent but significant differences were found only in comparison to the PS19 line (p < 0.05 for PS19/Tg4–42hom, p < 0.001 for Tg4–42hom) (Figure 2b).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At 9 months, both Tg4-42hom and PS19/Tg4-42hom mice showed impaired recognition memory, being unable to discriminate between novel and familiar objects, with DI close to zero and significantly lower than WT controls.

    “At 9 months, both Tg4–42hom and PS19/Tg4–42hom mice showed an impaired recognition memory, being unable to discriminate between the novel and familiar objects. These two lines showed a DI close to zero, and significantly lower than WT controls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aged transgenic lines displayed reduced entries and time spent in the platform zone compared to non-transgenic mice.

    “Aged transgenic lines displayed reduced entries and time spent in the platform zone when compared to non-transgenic mice (Figure 3l,o), and PS19/Tg4–42hom spent significantly less time in the platform zone than PS19 littermates (p < 0.05) (Figure 3o).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The spatial learning impairment observed in 5-month-old PS19/Tg4-42hom mice worsened as time progressed, as the aged group presented increased escape latency compared to both WT (p < 0.001) and the two parental lines (PS19: p < 0.001, Tg4-42hom: p < 0.05).

    “The spatial learning impairment observed in 5-month-old PS19/Tg4–42hom mice worsened as time progressed, as the aged group presented an increased escape latency compared to both WT (p < 0.001) and the two parental lines (PS19: p < 0.001, Tg4–42hom: p < 0.05) (Figure 3c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    While the two parental lines presented a progressive decrease over the three days of testing, PS19/Tg4-42hom mice displayed the poorest performance, significantly different from the two parental lines (p < 0.001).

    “While the two parental lines presented a progressive decrease over the three days of testing, PS19/Tg4–42hom mice displayed the poorest performance, significantly different from the two parental lines (p < 0.001) (Supplementary Figure S1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The WT group was usually swimming most slowly at 3 and 5 months.

    “While the WT group was the one usually swimming most slowly at 3 and 5 months, at 9 months, Tg4–42hom and PS19/Tg4–42hom lines showed a reduced average speed in the cue training, but no differences were observed in the acquisition training session (Supplementary Figure S2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Tg4-42hom and PS19/Tg4-42hom rotarod performance progressively worsened over time, with a further reduction in fall latencies at 9 months, resulting in significantly reduced values compared to both WT and PS19 groups (p < 0.001).

    “Tg4–42hom and PS19/Tg4–42hom performances in the accelerating rotarod task progressively worsened over time, with a further reduction in fall latencies at 9 months, resulting in significantly reduced values compared to both the WT and PS19 groups (p < 0.001) (Figure 2c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the aged groups, both Tg4-42hom and PS19/Tg4-42hom mice displayed spatial memory deficits, swimming a comparable amount of time among the four quadrants, while PS19 and WT mice showed a preference for the goal quadrant.

    “In the aged groups, both Tg4–42hom and PS19/Tg4–42hom mice displayed spatial memory deficits, swimming a comparable amount of time among the four quadrants, while PS19 and WT mice showed a preference for the goal quadrant (Figure 3f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In young animals, all transgenic lines showed a preference towards the novel object and comparable discrimination index (DI) values, although Tg4-42hom DI was significantly lower than WT controls (p < 0.05).

    “In young animals, all transgenic lines showed a preference towards the novel object and showed comparable discrimination index (DI) values, although Tg4–42hom DI resulted significantly lower than WT controls (p < 0.05), which might be attributed to the small sample variability.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    A deficit in the NOR task became obvious in aged mice, which was accompanied by the loss of ~60% of neurons in the distal CA1.

    “A deficit in this task became obvious in aged mice, which was accompanied by the loss of ~60% of neurons in the distal CA1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 9 months, abundant tau pathology with NFTs could be observed in the CA1 pyramidal layer, but with no significant difference between PS19 and PS19/Tg4-42hom mice.

    “At 9 months, abundant tau pathology with NFTs could be observed in the CA1 pyramidal layer, but with no significant difference between PS19 and PS19/Tg4–42hom mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PS19 mice seemed to perform slightly better than WT littermates on the accelerating rotarod, without reaching statistical significance.

    “With regard to the accelerating rotarod task, they even seemed to perform slightly better than WT littermates, however without reaching statistical significance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    PS19/Tg4-42hom mice presented increased neuron loss compared to Tg4-42hom animals (p < 0.01) in the distal part but not in the proximal part of the CA1 region at 3 months of age.

    “PS19/Tg4–42hom mice, expressing both transgenic tau and Aβ4–42, presented an increased neuron loss compared to Tg4–42hom animals (p < 0.01) in the distal part (Figure 4d and Supplementary Figure S5) but not in the proximal part of the CA1 region of the hippocampus at the age of 3 months (Figure 4c and Supplementary Figure S5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The lack of goal quadrant preference in 5-month-old PS19/Tg4-42hom mice indicates a spatial reference memory deficit at this time point, which could not be explained by differences in swimming speed.

    “Interestingly, this preference was not observed in 5-month-old PS19/Tg4–42hom mice (Figure 3e), indicating a spatial reference memory deficit at this time point, which could not be explained by differences in swimming speed (Figure 3g,h).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An up to 5-fold increased amyloid load was observed in 16-month-old Tg2576 mice that had been crossed with a tau transgenic line harboring a triple-mutant tau (G272V, P310L, R406W).

    “However, it has to be noted that an up to 5-fold increased amyloid load was observed in 16-month-old Tg2576 mice that have been crossed with a tau transgenic line harboring a triple-mutant tau (G272V, P310L, R406W) [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Ribe, 2005, Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice, Neurobiol. Dis. source

  • May combine two claims.

    Premisecitation

    A related model expressing only Aβ1-42 peptides with the rat preproenkephalin signal peptide (APP48) in the absence of APP overexpression developed intracellular Aβ lesions and presented with reduced hippocampal neuron numbers already at young age.

    “A related model expressing only Aβ1–42 peptides with the rat preproenkephalin signal peptide (APP48) in the absence of APP overexpression developed intracellular Aβ lesions and presented with reduced hippocampal neuron numbers already at young age [35].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Abramowski, 2012, Transgenic Expression of Intraneuronal Aβ42 But Not Aβ40 Leads to Cellular Aβ Lesions, Degeneration, and Functional Impairment without Typical Alzheimer’s Disease Pathology, J. Neurosci. source

  • May combine two claims.

    Interpretationown data

    Although Tg4-42hom and PS19/Tg4-42hom mice showed significant loss of distal CA1 pyramidal neurons already at 3 and 5 months, this is not reflected in a major impairment of recognition memory, at least not detectable in the NOR task carried out in the present study.

    “Though Tg4–42hom as well as PS19/Tg4–42hom mice showed a significant loss of distal CA1 pyramidal neurons already at 3 and 5 months, this is not reflected in a major impairment of recognition memory, at least not detectable in the NOR task carried out in the present study.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Double transgenic APP48/TAU58 mice showed neither evidence of increased levels of soluble Aβ, albeit data on Aβ levels in single transgenic APP48 mice were not reported, nor significant amounts of phospho-tau pathology.

    “Double transgenic mice showed neither evidence of increased levels of soluble Aβ, albeit data on Aβ levels in single transgenic APP48 mice were not reported, nor significant amounts of phospho-tau pathology [20].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Gomes, 2019, Aβ-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein, Acta Neuropathol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A substantially increased number of NFTs was detected in P301L tau transgenic mice following injection of fibrillary Aβ42 peptides.

    “A substantially increased number of NFTs was detected in P301L tau transgenic mice following injection of fibrillary Aβ42 peptides [30] and an induction of tau pathology was observed in the same line of tau transgenic mice after infusion of an Aβ-containing brain extract from a 24-month-old APP23 mouse [31].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Chen, 2001, Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils, Science source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Passive immunization against Aβ in the 3xTg mouse model reduced extracellular amyloid plaques and resulted in decreased tau pathology.

    “Related findings were reported by Vasconselos and colleagues, showing that pre-aggregated Aβ is able to induce fibrillization of tau both in vitro and in vivo [32], and interestingly, passive immunization against Aβ in the 3xTg mouse model not only reduced extracellular amyloid plaques but also resulted in decreased tau pathology [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Oddo, 2004, Abeta Immunotherapy Leads to Clearance of Early, but Not Late, Hyperphosphorylated Tau Aggregates via the Proteasome, Neuron source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Immunohistochemical staining sections were processed as previously described.

    “Sections were processed as previously described [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Wirths, 2002, Intraneuronal APP/A beta trafficking and plaque formation in beta-amyloid precursor protein and presenilin-1 transgenic mice, Brain Pathol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The Morris Water Maze assesses spatial reference memory.

    “The Morris Water Maze (MWM) was used to assess spatial reference memory [48] and was performed as previously described [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Morris, 1984, Developments of a water-maze procedure for studying spatial learning in the rat, J. Neurosci. Methods source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The rotarod task assesses motor performance and motor learning.

    “A computer-controlled rotarod system (TSE, Technical and Scientific Equipment) was used to assess motor performance and motor learning in the rotarod task [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Shiotsuki, 2010, A rotarod test for evaluation of motor skill learning, J. Neurosci. Methods source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Neuron loss in the CA3 and reduced DG volume have been described in P301S mice starting at 8 months.

    “The tau transgenic line did not present with loss of CA1 pyramidal neurons at the considered time points, but neuron loss in the CA3 and reduced DG volume have been described in P301S mice starting at 8 months [26,43].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Yoshiyama, 2007, Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model, Neuron source
    • cites [43] Liu, 2019, Inhibition of Calpain Protects Against Tauopathy in Transgenic P301S Tau Mice, J. Alzheimer’s Dis. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All data were analyzed using the Shapiro-Wilk test for normality to ensure that parametric tests can be applied.

    “All data have been analyzed using the Shapiro–Wilk test for normality to ensure that parametric tests can be applied.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Relative gene expression was quantified using murine β-Actin as a reference gene for normalization and the ΔΔCt method.

    “The relative expression of the genes of interest (GOIs) was performed using murine β-Actin as a reference gene for normalization, and were calibrated to a selected control group using the ΔΔCt method [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Livak, 2001, Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method, Methods source

  • May combine two claims.

    Interpretationown data

    The absence of obvious aggravation of tau pathology might suggest that the co-presence alone of Aβ4-42 and transgenic human tau and their additive singular detrimental effects could lead to the observed phenotypes in young mice.

    “The absence of obvious aggravation of tau pathology might suggest that the co-presence alone of Aβ4–42 and transgenic human tau and their additive singular detrimental effects could lead to the observed phenotypes in young mice.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The inverted grid task assesses neuromuscular abilities, vestibular function and muscle strength.

    “Neuromuscular abilities, vestibular function and muscle strength were tested with the inverted grid task [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Wirths, 2008, Deficits in working memory and motor performance in the APP/PS1ki mouse model for Alzheimer’s disease, Neurobiol. Aging source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The balance beam test assesses balance and fine motor coordination.

    “In order to assess balance and fine motor coordination, the balance beam test was conducted [46].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Luong, 2011, Assessment of motor balance and coordination in mice using the balance beam, J. Vis. Exp.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

51 of 51

  • The paper relies on this without support.

    Aggravation of tau pathology has been reported repeatedly in a variety of APP/tau transgenic lines, and the presence of Aβ peptides leads to an aggravation of an existing tau pathology in a variety of transgenic AD mouse models.

    “As an aggravation of tau pathology has been reported repeatedly in a variety of APP/tau transgenic lines”
    “As it has been shown previously that the presence of Aβ peptides leads to an aggravation of an existing tau pathology in a variety of transgenic AD mouse models”
1 of 1

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Neuron-counting methods omit the reported 9-month analysis

    Minor

    The methods specify CA1 neuron-loss assessment in 3- and 5-month-old mice, while the results report neuron-number comparisons at 9 months as well.

  • PS19 tau mutation is identified as both P310S and P301S

    Minor

    The methods describe the PS19 mice as carrying a P310S mutation, but the strain identifier in the same paragraph specifies P301S. The paper also identifies PS19 as a P301S model elsewhere.

  • Recognition-memory summary conflicts with the aged-group result

    Minor

    The results first say there was no significant recognition-memory alteration in the bigenic mice, but later say the 9-month-old bigenic group had a discrimination index significantly below WT controls.

3 of 3

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Authors
Zampar, S., & Wirths, O.
Affiliations
Universitätsmedizin Göttingen (DE)
Corresponding author
Wirths, Oliver
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2021-05-14
Volume
22
Issue
10
Pages
5191
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms22105191
PMC
PMC8156793
OpenAlex
W3160373154
Semantic Scholar
901f0c2b5c0ef6be85cf65472e97bf850175ab25
Cited by
18
References
50
Citations by year
2026: 2 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 2
FWCI
1.43
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
Funders
  • Alzheimer Forschung Initiative (16013)
  • Alzheimer Stiftung Göttingen (-)
  • Gerhard Hunsmann Stiftung (T0323-28.817)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, double transgenic mouse model, amyloid-beta, tau phosphorylation, neurofibrillary tangles, motor performance, spatial memory impairment, CA1 pyramidal neurons, hippocampus, soluble amyloid-beta
MeSH terms
Motor Disorders, Alzheimer Disease, Animals, Behavior, Animal, Disease Models, Animal, Female, Humans, Male, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Amyloid beta-Peptides, tau Proteins, Mice

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-24.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-24.

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