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Cited by 142Alzheimer's disease research and treatmentsMedicinal Plants and NeuroprotectionDementia and Cognitive Impairment Research

Galantamine Slows Down Plaque Formation and Behavioral Decline in the 5XFAD Mouse Model of Alzheimer’s Disease

Open access
Bhattacharya, Soumee, Haertel, Christin, Maelicke, Alfred, Montag, Dirk·2014·PLoS ONE
DOI 10.1371/journal.pone.0089454PMC PMC3931790
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Abstract

The plant alkaloid galantamine is an established symptomatic drug treatment for Alzheimer's disease (AD), providing temporary cognitive and global relief in human patients. In this study, the 5X Familial Alzheimer's Disease (5XFAD) mouse model was used to investigate the effect of chronic galantamine treatment on behavior and amyloid β (Aβ) plaque deposition in the mouse brain. Quantification of plaques in untreated 5XFAD mice showed a gender specific phenotype; the plaque density increased steadily reaching saturation in males after 10 months of age, whereas in females the density further increased until after 14 months of age. Moreover, females consistently displayed a higher plaque density in comparison to males of the same age. Chronic oral treatment with galantamine resulted in improved performance in behavioral tests, such as open field and light-dark avoidance, already at mildly affected stages compared to untreated controls. Treated animals of both sexes showed significantly lower plaque density in the brain, i.e., the entorhinal cortex and hippocampus, gliosis being always positively correlated to plaque load. A high dose treatment with a daily uptake of 26 mg/kg body weight was tolerated well and produced significantly larger positive effects than a lower dose treatment (14 mg/kg body weight) in terms of plaque density and behavior. These results strongly support that galantamine, in addition to improving cognitive and behavioral symptoms in AD, may have disease-modifying and neuroprotective properties, as is indicated by delayed Aβ plaque formation and reduced gliosis.

AI snapshot

Written from the paper’s full text.

TL;DR

Chronic oral galantamine in 5XFAD mice improved some behavioral deficits and reduced amyloid plaque density in the hippocampus and entorhinal cortex, with a high dose producing larger effects than a low dose. The authors conclude galantamine may have disease-modifying and neuroprotective properties in addition to symptomatic benefits.

Key findings

  • Untreated 5XFAD mice showed sex-specific plaque progression: males reached saturation at 10 months, while females continued increasing after 14 months; females consistently had higher plaque density, and plaque density was always higher in entorhinal cortex than hippocampus. Plaques were detectable at 2 months.
  • Chronic galantamine improved open field behavior and partially normalized light-dark avoidance, with high dose (26 mg/kg/day) significantly more effective than low dose (14 mg/kg/day). It did not normalize the reduced startle response or prepulse inhibition, and it increased freezing in fear conditioning irrespective of genotype.
  • High-dose galantamine significantly reduced plaque density versus untreated controls (p≤0.0001): hippocampus ~19% fewer plaques in males and ~25% fewer in females; entorhinal cortex ~32% fewer in males and ~33% fewer in females.
  • Plaque density strongly correlated with GFAP-positive reactive astrocyte density (R² = 0.62; ANOVA F(1,21) = 34.232; p<0.0001), suggesting reduced gliosis with treatment.

Methods

  • 5XFAD transgenic mice and non-transgenic littermates were used. Untreated behavioral analysis was performed at 7 months; treatment began at 10–12 weeks for 2 months, with behavioral testing at 4–5 months, followed by histological plaque quantification.
  • Galantamine hydrobromide was given in drinking water: low dose 12 mg/l for 4 weeks then 60 mg/l; high dose 36 mg/l for 4 weeks then 120 mg/l, yielding daily uptake of 14 mg/kg (low) and 26 mg/kg (high). Behavioral tests included open field, light-dark avoidance, O-maze, rota-rod, grip strength, startle/PPI, and fear conditioning.
  • Brains were analyzed with thioflavin-S staining for plaques, GFAP for reactive astrocytes, 4G8 for β-amyloid, isolectin GSA for microglia, and Nissl staining. Statistics used ANOVA with genotype, sex, and treatment factors, post hoc tests, repeated measures ANOVA for selected behavioral tests, and regression for plaque-astrocyte correlation.

Limitations

  • The paper states that galantamine did not modify the poor startle response or lack of prepulse inhibition; the authors speculate this may reflect a very early event not curable by later treatment or insufficient dosage/duration. It also states that increased freezing in fear conditioning could be a side effect on anxiety.
  • The paper states that mechanisms of galantamine action were not fully resolved and suggests future quantification of total Aβ and its isoforms to address whether effects reflect reduced deposition versus clearance.
  • Evident from the text: findings are limited to a mouse model, use only two dose regimens, and do not include human data or direct measures of soluble Aβ oligomers; sex differences in plaque load are reported but not mechanistically explained.

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

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0089454

Cites

62 of 62 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

0 of 57 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In fear conditioning, 5XFAD transgenic mice display significantly more freezing in the context.

    “5XFAD transgenic mice (8 males, 10 females) displayed significantly more freezing in the context (F(1,32) = 4.542, p = 0.0409) but also in the neutral surrounding (not significant, p = 0.1641)”
    Quote in the paperNot a substantial claim
  • Findingown data

    In the open field, 7-month-old 5XFAD transgenic mice spend significantly less time in the corners compared to control littermates.

    “In the open field, transgenic mice spend significantly less time in the corners (F(1,28) = 5.245, p = 0.0297, post hoc Fisher’s PLSD p = 0.0311) compared to control littermates (Figure 3D).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In the light-dark avoidance paradigm, 7-month-old 5XFAD transgenic mice spend more time in the illuminated part.

    “and spend more time in the illuminated part (Figure 3F) (F(1,28) = 9.026, p = 0.0056; post hoc Fisher’s PLSD p = 0.0067).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In non-transgenic control littermates, plaques were never observed at any age.

    “In control non-transgenic littermates, plaques were never observed at any age.”
    Quote in the paperNot a substantial claim
  • Findingown data

    When tested for memory, 5XFAD mice still have longer latency to enter the dark compartment than non-transgenic littermates.

    “The latency with which transgenic mice entered the dark compartment when tested for memory was still longer as of their non-transgenic littermates (F(1,28) = 4.345, p = 0.0464; post hoc Fisher’s PLSD p = 0.0491).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 34
  • May combine two claims. 17
  • The quote only partly states this claim. 7

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

    Findingown data

    The galantamine treatment scheme resulted in a daily uptake of 14 mg/kg body weight (low dose) and 26 mg/kg body weight (high dose) during the last phase of treatment.

    “This application scheme resulted in the daily uptake of 14 mg/kg body weight (low dose) and 26 mg/kg body weight during the last phase of the treatment (Figure 4B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    High dose galantamine (26 mg/kg daily) was tolerated well and produced significantly larger positive effects than low dose (14 mg/kg) in terms of plaque density and behavior.

    “A high dose treatment with a daily uptake of 26 mg/kg body weight was tolerated well and produced significantly larger positive effects than a lower dose treatment (14 mg/kg body weight) in terms of plaque density and behavior.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    Gliosis is always positively correlated to plaque load in 5XFAD mice.

    “gliosis being always positively correlated to plaque load.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In untreated 5XFAD mice, plaque density increases with age and reaches saturation in males after 10 months, whereas in females it continues to increase after 14 months.

    “Quantification of plaques in untreated 5XFAD mice showed a gender specific phenotype; the plaque density increased steadily reaching saturation in males after 10 months of age, whereas in females the density further increased until after 14 months of age.”
    • Also stated in: § Quantitative Analysis of Plaque Deposition in 5XFAD Mice · plain
      “Maximal density was not reached even at 14 months of age in females, whereas in males no increase in plaque density was observed after 10 months of age.”
    • Also stated in: § Quantitative Analysis of Plaque Deposition in 5XFAD Mice · plain
      “In males, plaque density increased in both brain areas and reached saturation at 10 months of age. In female mice, plaque accumulation was faster, reached higher levels, and continued to increase after 14 months of age.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    In 5XFAD mice, β amyloid deposits are usually associated with reactive astrocytes and microglia.

    “Furthermore, β amyloid deposits are usually associated with reactive astrocytes identified by immunohistochemical staining for GFAP (Figure 1G) and microglia identified by isolectin GSA staining (Figure 1H).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    In 7-month-old 5XFAD mice, body weight is approximately 10% less than in non-transgenic littermates, both before and after behavioral tests.

    “the body weight of transgenic mice was approximately 10% less than that of their control littermates, both, before and after the behavioral tests (Figure 3A)”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Maximum and average grip strength are significantly higher in male mice compared to females.

    “As expected, the maximum and average grip strength were significantly higher for males compared to females (F(1,28) = 32.038, p<0.0001; F(1,28) = 25.969, p<0.0001, respectively)”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    In the light-dark avoidance paradigm, mock-treated 4-5-month-old 5XFAD transgenic mice show fewer transitions than non-transgenic mice.

    “mock-treated transgenic mice showed less transitions”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Galantamine treatment elevated the corner preference of 4-5-month-old 5XFAD transgenic mice to normal levels in a dose-dependent manner.

    “treatment with galantamine elevated the preference for the corners to normal levels in a dose dependent manner (Figure 5A)”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Galantamine treatment resulted in increased freezing during fear conditioning irrespective of genotype in 4-5-month-old mice.

    “treatment with galantamine resulted in increased freezing irrespective of the genotype”
    • Also stated in: § Galantamine Treatment Affects Behavior and Plaque Deposition · plain
      “the treatment increased the overall freezing behavior in the fear conditioning paradigm irrespective of the genotype”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    In the open field, 4-5-month-old 5XFAD transgenic mice show reduced avoidance of the center compared to non-transgenic mice.

    “reduced avoidance of the center by transgenic mice”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Galantamine treatment partially improved light-dark avoidance behavior in 4-5-month-old 5XFAD transgenic mice.

    “and partially in the light-dark avoidance paradigm”
    • Also stated in: § Galantamine Treatment Affects Behavior and Plaque Deposition · plain
      “the abnormal light-dark avoidance behavior of 5XFAD mice was partially normalized.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    The latency at the second encounter with the test box was reduced irrespective of genotype or treatment in 4-5-month-old mice.

    “The latency at the second encounter with the test box was reduced irrespective of genotype or treatment”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    GFAP-positive reactive astrocytes are usually found in association with Aβ plaques.

    “GFAP-positive reactive astrocytes are usually found in association with Aβ plaques (Figure 1).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    In the light-dark avoidance paradigm, mock-treated 4-5-month-old 5XFAD transgenic mice show longer presence in the illuminated compartment than non-transgenic mice.

    “and longer presence in the illuminated compartment”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    During hippocampus-dependent contextual fear conditioning, 5XFAD mice show significantly more freezing in the context and in the neutral surrounding.

    “During hippocampus dependent contextual fear conditioning we observed significantly more freezing of 5XFAD mice in the context but also in the neutral surrounding.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Galantamine exerts neuroprotective effects in cell systems by anti-apoptotic action, modulating amyloid precursor processing, and inhibiting β-amyloid aggregation and cytotoxicity.

    “Furthermore, galantamine exerts in cell systems neuroprotective effects by anti-apoptotic action [13], by modulating amyloid precursor processing [14], and by inhibiting β-amyloid aggregation and cytotoxicity [15].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] M Villarroya, 2007, An update on the pharmacology of galantamine, Expert Opin Investig Drugs source

      Not checked in the free run.

    • cites [14] SC Lenzken, 2007, Nicotinic component of galantamine in the regulation of amyloid precursor protein processing, Chem Biol Interact source

      Not checked in the free run.

    • cites [15] B Matharu, 2009, Galantamine inhibits beta-amyloid aggregation and cytotoxicity, J Neurol Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The 5XFAD mouse model recapitulates a variety of AD features, including working memory impairment, reduced anxiety, extensive extracellular plaque formation beginning at 2 months of age, and selective neuron loss, making it suitable for early-onset AD research.

    “This model recapitulates a variety of AD features, including working memory impairment, reduced anxiety, extensive extracellular plaque formation beginning at 2 months of age, and selective neuron loss, making it a suitable research model for early-onset AD [20]–[24].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20]–[24]

      Not checked in the free run.

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

    Study design and conductnone given

    Behavioral tests were conducted by an experimenter not aware of the genotype.

    “by an experimenter not aware of the genotype.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    For the behavioral analysis, sex- and age-matched littermate wild-type mice were used as controls.

    “For the behavioral analysis, sex- and age-matched littermate wild-type mice were used as controls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Galantamine may have disease-modifying and neuroprotective properties in AD, in addition to improving cognitive and behavioral symptoms, as indicated by delayed Aβ plaque formation and reduced gliosis.

    “These results strongly support that galantamine, in addition to improving cognitive and behavioral symptoms in AD, may have disease-modifying and neuroprotective properties, as is indicated by delayed Aβ plaque formation and reduced gliosis.”
    • Also stated in: § Introduction · plain
      “Our data show that galantamine slows down plaque deposition and improves behavioral performance.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    In order to normalize regional bias in plaque load, 12 sections 200 μm apart from each other were selected from all animals in every experiment.

    “In order to normalize regional bias in plaque load, 12 sections 200 µm apart from each other were selected from all animals in every experiment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Long-term galantamine treatment of AD patients slows down cognitive and global decline and reduces behavioral symptoms, most strongly in patients with moderate or advanced forms.

    “Long-term galantamine treatment of AD patients slows down cognitive and global decline [17] and reduces behavioral symptoms, most strongly in patients with moderate or advanced forms of the disease [18].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] ÅK Wallin, 2011, Galantamine treatment in Alzheimer’s disease: response and long-term outcome in a routine clinical setting, Neuropsychiatr Dis Treat source

      Not checked in the free run.

    • cites [18] S Kavanagh, 2011, Galantamine and behavior in Alzheimer disease: analysis of four trials, Acta Neurol Scand source

      Not checked in the free run.

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

    Premisecitation

    Long-term positive effects of galantamine are reflected in PET measurements.

    “Similar long-term positive effects are also reflected in PET measurements [19].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] C Keller, 2011, Long-term effects of galantamine treatment on brain functional activities as measured by PET in Alzheimer’s disease patients, J Alz Dis source

      Not checked in the free run.

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

    Premisecitation

    The acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine serve as first-line symptomatic drug treatment in mild to moderate Alzheimer's dementia.

    “The acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine serve as first-line symptomatic drug treatment in mild to moderate Alzheimer’s dementia [8].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] L Patel, 2011, Combination therapy for Alzheimer’s disease, Drugs Aging source

      Not checked in the free run.

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

    Premisecitation

    Chronic low-level stimulation of nicotinic receptors might up-regulate their expression, slow down neurodegeneration, and confer protection against β-amyloid toxicity.

    “Chronic low-level stimulation of nicotinic receptors might up-regulate their expression [10], slow down neurodegeneration [11], and confer protection against β-amyloid toxicity [12].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10] X Peng, 1997, Chronic nicotine treatment up-regulates alpha3 and alpha7 acetylcholine receptor subtypes expressed by the human neuroblastoma cell line SH-SY5Y, Mol Pharmacol source

      Not checked in the free run.

    • cites [11] JA Court, 1994, CNS nicotine receptors. Possible therapeutic targets in neurodegenerative disorders, CNS Drugs

      Not checked in the free run.

    • cites [12] T Kihara, 1998, Stimulation of alpha4beta2 nicotinic acetylcholine receptors inhibits beta-amyloid toxicity, Brain Res source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Increased production of certain Aβ species, their aggregation, and deposition as insoluble plaques is regarded as an early and key pathology in AD.

    “Increased production of certain Aβ species, their aggregation, and deposition as insoluble plaques is regarded as an early and key pathology in the development of AD [2].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] M Citron, 2004, Strategies for disease modification in Alzheimer’s disease, Nat Rev Neurosci source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Therapeutic strategies to reverse or prevent Aβ deposits could lead to partial functional restoration of neural circuits.

    “At a systemic level, therapeutic strategies to reverse or prevent Aβ deposits could lead to partial functional restoration of neural circuits [5].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] RB Knowles, 1999, Plaque-induced neurite abnormalities: Implications for disruption of neural networks in Alzheimer’s disease, Proc Natl Acad Sci USA source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Most AD treatment approaches aim at prevention or reversal of Aβ plaque deposition.

    “Therefore, most AD treatment approaches aim at prevention or reversal of Aβ plaque deposition [6], [7].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] S Schilling, 2008, Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer’s disease-like pathology in vivo, Nat Med source

      Not checked in the free run.

    • cites [7] M Citron, 2010, Alzheimer’s disease: strategies for disease modification, Nat Rev Drug Discov source

      Not checked in the free run.

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

    Study design and conductown data

    Aβ deposits are easily identified by immunohistochemistry or by thioflavin-S staining in 5XFAD mice.

    “However, Aβ deposits are easily identified by immunohistochemistry (Figure 1D) or by thioflavin-S staining (Figure 1F).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Aβ plaques may serve as reservoirs of soluble Aβ oligomers injuring surrounding neurites and synapses.

    “Aβ plaques may serve as reservoirs of soluble Aβ oligomers injuring surrounding neurites and synapses [3], [4].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] RM Koffie, 2009, Oligomeric amyloid β associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques, Proc Natl Acad Sci USA source

      Not checked in the free run.

    • cites [4] TL Spires, 2005, Dendritic spine abnormalities in APP transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy, J Neurosci source

      Not checked in the free run.

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

    Premisecitation

    The amyloid cascade theory provides a rationale for many features of AD including pathological markers, phenotypes caused by autosomal dominant disease genes, and risk conferred by APOE gene status.

    “The amyloid cascade theory provides a rationale for many features of the disease including the pathological markers, the phenotypes caused by autosomal dominant disease genes, and the risk conferred by the APOE gene status [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] E Karran, 2011, The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics, Nat Rev Drug Discov source

      Not checked in the free run.

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

    Study design and conductcitation

    An improved thioflavin-S staining protocol was used to ensure reduced photobleaching and tissue damage.

    “An improved thioflavin-S staining protocol [32] was used to ensure reduced photobleaching and tissue damage.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] A Sun, 2002, Comparative analysis of an improved thioflavin-s stain, Gallyas silver stain, and immunohistochemistry for neurofibrillary tangle demonstration on the same sections, J Histochem Cytochem source

      Not checked in the free run.

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

    Premisecitation

    A number of current strategies involved in treatment and/or prevention of AD progression are directed against the deposition of plaques.

    “a number of current strategies e.g. glutaminyl cyclase inhibition and immunotherapy, involved in the treatment and/or prevention of AD progression are indeed directed against the deposition of plaques [6], [57].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] S Schilling, 2008, Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer’s disease-like pathology in vivo, Nat Med source

      Not checked in the free run.

    • cites [57] RB Demattos, 2012, A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer’s disease mice, Neuron source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    The positive effect of galantamine in restoring certain normal behavioral traits could result from its acetylcholinesterase inhibitor activity.

    “the positive effect of galantamine in restoring certain normal behavioral traits could result from its acetylcholinesterase inhibitor activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] M Singh, 2013, Acetylcholinesterase inhibitors as Alzheimer therapy: From nerve toxins to neuroprotection, Eur J Med Chem source

      Not checked in the free run.

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

    Premisecitation

    A higher plaque density in female transgenic mice has also been noted in other AD mouse models.

    “A higher plaque density in female transgenic mice has also been noted in other AD mouse models [33]–[35]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33]–[35]

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Chronic galantamine treatment had positive effects on certain behavioral tasks but could not rescue all abnormalities in 5XFAD mice.

    “The chronic treatment with galantamine had positive effects on certain behavioral tasks but could not rescue all the abnormalities.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    A previous study by Unger et al. reported that galantamine at 2 mg/kg injected subcutaneously for 10 days had no effect on the levels of soluble or insoluble forms of Aβ in 10-month-old Tg2576 mice.

    “A previous study by Unger et al. [56] reported that galantamine at a concentration of 2mg/kg injected subcutaneously for 10 days had no effect on the levels of soluble or insoluble forms of Aβ in 10 months old Tg2576 mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] C Unger, 2006, Effect of subchronic treatment of memantine, galantamine, and nicotine in the brain of Tg2576 (APPswe) transgenic mice, J Pharmacol Exp Ther source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced plaque formation could have a role in preventing further cortical atrophy in AD brain, as plaque deposition has been correlated with accelerated cortical atrophy.

    “reduced plaque formation could have a role in preventing further cortical atrophy in AD brain, as plaque deposition in multiple studies has been correlated with accelerated cortical atrophy [58], [59].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [58] JA Becker, 2011, Amyloid-β associated cortical thinning in clinically normal elderly, Ann Neurol source

      Not checked in the free run.

    • cites [59] G Chételat, 2012, Accelerated cortical atrophy in cognitively normal elderly with high β-amyloid deposition, Neurol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    5XFAD mice at seven months show several behavioral deficits, a phenotype with mild cognitive impairment, and progressive amyloid plaque deposition.

    “5XFAD mice show at the age of seven months several behavioral deficits, a phenotype with mild cognitive impairment, and progressive amyloid plaque deposition”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Chronic treatment with galantamine significantly delayed progression of amyloid plaque deposition and improved certain behavioral symptoms associated with AD in the 5XFAD model.

    “we report a significantly delayed progression of amyloid plaque deposition and improvement of certain behavioral symptoms associated with AD in the 5XFAD Alzheimer’s disease model after chronic treatment with galantamine.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Galantamine binds to amyloid oligomers leading to a significant conformational change at the turn region (Asp23-Gly29) disrupting interactions between individual β strands and promoting a nontoxic conformation of Aβ (1-40) to prevent the formation of neurotoxic oligomers.

    “galantamine binds to amyloid oligomers leading to a significant conformational change at the turn region (Asp23-Gly29) disrupting interactions between individual β strands and promoting a nontoxic conformation of Aβ (1–40) to prevent the formation of neurotoxic oligomers [55].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] PPN Rao, 2013, Investigating the binding interactions of galantamine with b-amyloid peptide, Bioorg Med Chem Lett source

      Not checked in the free run.

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

    Premisecitation

    In AD, loss of pyramidal cells in lamina 2 of the entorhinal cortex and in the CA1 region of the hippocampus was described.

    “in AD loss of pyramidal cells in lamina 2 of the entorhinal cortex and in the CA1 region of the hippocampus was described [39]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] T Gomez-Isla, 1996, Profound Loss of Layer II Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer’s Disease, J Neurosci source

      Not checked in the free run.

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

    Premisecitation

    In a similar APP/PS1 transgenic mouse model, sensorimotor gating deficits were reported for aged mice using prepulse inhibition of the acoustic startle response.

    “In a similar APP/PS1 transgenic mouse model, sensorimotor gating deficits were reported for aged mice using prepulse inhibition of the acoustic startle response [51].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] H Wang, 2012, Sensorimotor gating and memory deficits in an APP/PS1 double transgenic mouse model of Alzheimer’s disease, Beh Brain Res source

      Not checked in the free run.

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

    Premisecitation

    Contextual fear conditioning after 1 footshock is normal in 5XFAD mice younger than 4 months, but impaired in 6-month-old animals, which could be overcome using 3-5 footshocks.

    “It has also been shown previously, that contextual fear conditioning after 1 footshock is normal in 5XFAD mice younger than 4 months, but impaired in the 6 month old animals, which could be overcome using 3–5 footshocks [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] R Kimura, 2009, Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model, Neurobiol Dis source

      Not checked in the free run.

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

    Premisecitation

    Several other AD mouse models display normal motor coordination and grip strength.

    “Likewise, several other AD mouse models display normal motor coordination and grip strength [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] SJ Webster, 2013, Comprehensive behavioral characterization of an APP/PS-1 double knock-in mouse model of Alzheimer’s disease, Alzheimers Res Ther source

      Not checked in the free run.

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

    Premisecitation

    In humans, the dosage of galantamine is increased with time to minimize negative side effects.

    “To mimic the treatment regimen in humans, where the dosage is increased with time to minimize negative side effects [53]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] B Seltzer, 2010, Galantamine-ER for the treatment of mild-to-moderate Alzheimer’s disease, Clin Interv Aging

      Not checked in the free run.

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

    Premisecitation

    5XFAD and several other AD mouse models show a tendency to spend longer times in the center of the open field or the open arms of the elevated plus maze.

    “similar to the tendency to spend longer times in the center of the open field or the open arms of the elevated plus maze reported previously for 5XFAD [22], [23] and several other AD mouse models [45], [46].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22] V Shukla, 2013, A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer’s disease phenotypes in model mice, FASEB J source

      Not checked in the free run.

    • cites [23] O Wirths, 2010, Identification of low molecular weight pyroglutamate Aβ oligomers in Alzheimer’s disease: a novel tool for therapy and diagnosis, J Biol Chem source

      Not checked in the free run.

    • cites [45] Y Tong, 2010, COL25A1 triggers and promotes Alzheimer’s disease-like pathology in vivo, Neurogenet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    5XFAD mice do not exhibit sensory-motoric impairments in string hanging and beam walking before 9 months or abnormal rota-rod coordination before 12 months.

    “confirming previous studies reporting that 5XFAD mice do not exhibit sensory-motoric impairments in string hanging and beam walking before 9 months [24] or abnormal rota-rod coordination before 12 months [22] of age.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] S Jawhar, 2012, Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Aβ aggregation in the 5XFAD mouse model of Alzheimer’s disease, Neurobiol Aging 33

      Not checked in the free run.

    • cites [22] V Shukla, 2013, A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer’s disease phenotypes in model mice, FASEB J source

      Not checked in the free run.

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

    Premisecitation

    Galantamine is known to have side effects with respect to cholinergically mediated gastrointestinal symptoms like other cholinesterase inhibitors.

    “Galantamine is known to have side effects with respect to cholinergically mediated gastrointestinal symptoms like other cholinesterase inhibitors [52].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] D Prvulovic, 2010, Galantamine for Alzheimer’s disease. Expert Opin, Drug Metab Toxicol source

      Not checked in the free run.

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

    Premisecitation

    Reduced hippocampus-dependent trace fear conditioning, but normal hippocampus-independent delay fear conditioning, comparable to the tone memory assayed here, has been reported for 5XFAD mice.

    “Reduced hippocampus dependent trace fear conditioning, but normal hippocampus independent delay fear conditioning, which is comparable to the tone memory assayed here, has been reported for 5XFAD mice [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] M Ohno, 2006, Temporal memory deficits in Alzheimer’s mouse models: rescue by genetic deletion of BACE1, Eur Jour Neurosci source

      Not checked in the free run.

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

    Premisecitation

    According to the cholinergic hypothesis, decreased production of acetylcholine or amplified acetylcholinesterase activity results in impairment of cholinergic transmission, in turn leading to loss of intellectual abilities.

    “According to the cholinergic hypothesis, a decreased production of acetylcholine or an amplified acetylcholinesterase activity results in impairment of the cholinergic transmission, in turn leading to the loss of intellectual abilities [54].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] M Singh, 2013, Acetylcholinesterase inhibitors as Alzheimer therapy: From nerve toxins to neuroprotection, Eur J Med Chem source

      Not checked in the free run.

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

    Premisecitation

    Suppression of sensorimotor gating has been repeatedly reported in AD patients.

    “Suppression of sensorimotor gating has been repeatedly reported in AD patients [49], [50].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [49] F Jessen, 2001, Sensory Gating Deficit Expressed by a Disturbed Suppression of the P50 Event-Related Potential in Patients With Alzheimer’s Disease, Am J Psychiatry source

      Not checked in the free run.

    • cites [50] I Cancelli, 2006, Sensory gating deficit assessed by P50/Pb middle latency event related potential in Alzheimer’s disease, J Clin Neurophys source

      Not checked in the free run.

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

    Interpretationcitation

    Our paradigm used 2 footshocks, which may have been sufficient to overcome a slight deficit.

    “Our paradigm used 2 footshocks, which may have been sufficient to overcome a slight deficit.”
    Quote in the paperNot a substantial claim
54 of 54

  • The paper relies on this without support.

    The pattern of progressive plaque deposition and development in 5XFAD mice had not been systematically described before this study.

    “However, the pattern of progressive plaque deposition and development has not yet been described in a systematic manner.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Female microglia exhibit heightened plaque pathology compared to age-matched male microglia in the 5xFAD model.

    “female microglia exhibited heightened plaque pathology compared to age-matched male microglia in the 5xFAD model.70,71”

    From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [70]

    The Results section, “Quantitative Analysis of Plaque Deposition in 5XFAD Mice” (page unavailable), reports more plaques in female than male 5XFAD mice at comparable ages. It also shows microglia associated with plaques, but does not compare plaque pathology in female and male microglia; the sex comparison is between mice, not microglia. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Female 5XFAD mice have increased BACE1 activity, leading to increased amyloid plaque burden compared to male 5XFAD mice.

    “Females also appear to have increased BACE1 activity, a β-secretase processing enzyme which cleaves pAPP and produces pathogenic Aβ fragments [40,41], ultimately leading to increased amyloid plaque burden compared to male 5XFAD mice [41,42].”

    From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [42]

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • ConsistentF(1, 28) = 15.912reported p = .0004 · recomputed p < .001

    “F(1,28) = 15.912, p = .0004”

  • ConsistentF(1, 28) = 136797reported p < .0001 · recomputed p < .001

    “F(1,28) = 136,797, p < .0001”

  • ConsistentF(1, 28) = 24.426reported p < .0001 · recomputed p < .001

    “F(1,28) = 24.426, p < .0001”

  • ConsistentF(1, 28) = 147.182reported p < .0001 · recomputed p < .001

    “F(1,28) = 147.182, p < .0001”

  • ConsistentF(1, 28) = 32.038reported p < .0001 · recomputed p < .001

    “F(1,28) = 32.038, p < .0001”

  • ConsistentF(1, 28) = 25.969reported p < .0001 · recomputed p < .001

    “F(1,28) = 25.969, p < .0001”

  • ConsistentF(1, 28) = 5.245reported p = .0297 · recomputed p = .030

    “F(1,28) = 5.245, p = .0297”

  • ConsistentF(1, 28) = 9.077reported p = .0054 · recomputed p = .005

    “F(1,28) = 9.077, p = .0054”

  • ConsistentF(1, 28) = 9.026reported p = .0056 · recomputed p = .006

    “F(1,28) = 9.026, p = .0056”

  • ConsistentF(1, 28) = 8.635reported p = .0065 · recomputed p = .007

    “F (1,28) = 8.635, p = .0065”

  • ConsistentF(1, 28) = 4.345reported p = .0464 · recomputed p = .046

    “F(1,28) = 4.345, p = .0464”

  • ConsistentF(1, 24) = 23679reported p < .0001 · recomputed p < .001

    “F(1,24) = 23,679, p < .0001”

  • ConsistentF(1, 24) = 15.319reported p = .0007 · recomputed p < .001

    “F(1,24) = 15.319, p = .0007”

  • ConsistentF(1, 28) = 4.578reported p = .0412 · recomputed p = .041

    “F(1,28) = 4.578, p = .0412”

  • ConsistentF(1, 196) = 11.488reported p = .0021 · recomputed p < .001

    “F(1,196) = 11.488, p = .0021”

    The paper states a correction for multiple tests

  • ConsistentF(1, 32) = 4.542reported p = .0409 · recomputed p = .041

    “F(1,32) = 4.542, p = .0409”

16 of 16

Self-check

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

Self-check results appear here once an independent check has confirmed them.

Cites

Flagged first, then by citations

1 of the 63 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. JA Court, 1994, CNS nicotine receptors. Possible therapeutic targets in neurodegenerative disorders, CNS Drugs, 2, 216
  2. RJ Vassar, 2005, 5XFAD Tg mice that express five FAD mutations have high-cerebral aβ42 levels, rapid amyloid deposition, and intraneuronal aβ, Soc Neurosci Abstr, 587, 2

Cited by

Sorted by citations

Related

Authors
Bhattacharya, S., Haertel, C., Maelicke, A., & Montag, D.
Affiliations
Leibniz Institute for Neurobiology (DE)
Corresponding author
Montag, Dirk
ORCID
Montag, Dirk
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-02-21
Volume
9
Issue
2
Pages
e89454
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0089454
PMC
PMC3931790
OpenAlex
W2037958764
Semantic Scholar
d508af336fe1e788f67129cdba6021b2b30f8426
Cited by
142
References
63
Citations by year
2026: 7 · 2025: 11 · 2024: 11 · 2023: 14 · 2022: 13 · 2021: 17 · 2020: 15 · 2019: 14 · 2018: 11 · 2017: 7 · 2016: 11 · 2015: 9 · 2014: 2
FWCI
6.43
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
Funders
Bundesministerium für Bildung und Forschung
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plants and Neuroprotection
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
galantamine, Alzheimer's disease, 5xFAD mice, amyloid plaques, plaque deposition, behavioral decline, sex differences, gliosis, entorhinal cortex, hippocampus, disease-modifying therapy, neuroprotection, dose-dependent effects, plant alkaloids
MeSH terms
Alzheimer Disease, Animals, Behavior, Animal, Brain, Cholinesterase Inhibitors, Disease Models, Animal, Female, Galantamine, Male, Neurons, Sex Factors, Maze Learning, Mice, Plaque, Amyloid

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 2026-10-10.

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

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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