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

The DOI matches its Crossref record; 62 of the 63 references it cites were found in a registry or an index; none of the 57 sources its claims cite is checked for support yet.

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

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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.

Overview

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

Figures

Figure 1 Brain morphology, amyloid plaque formation, gliosis, and microglial activation in 5XFAD transgenic mice. Coronal brain sections from 22-week-old wild-type control littermates (A, C, E) and 5XFAD transgenic mice (B, D, F, G, H) were subjected to Nissl staining (A, B) revealing similar brain morphology. Amyloid β immunohistochemistry (C, D) or thioflavin-S staining (E, F) detect numerous amyloid plaques in 5XFAD mice (D, F), whereas wild-type control brains (C, E) are completely devoid of plaques. GFAP immunohistochemistry (activated astrocytes, red in G) or GSA-lectin (activated microglia, red in H) in combination with thioflavin S staining (green in G and H) revealed plaques surrounded by reactive astrocytes and associated with activated microglia in 5XFAD mice. Scale bars: 500 µm (A–F), 250 µm (G, H), and 100 µm (inset in G and H).
Figure 1 Brain morphology, amyloid plaque formation, gliosis, and microglial activation in 5XFAD transgenic mice. Coronal brain sections from 22-week-old wild-type control littermates (A, C, E) and 5XFAD transgenic mice (B, D, F, G, H) were subjected to Nissl staining (A, B) revealing similar brain morphology. Amyloid β immunohistochemistry (C, D) or thioflavin-S staining (E, F) detect numerous amyloid plaques in 5XFAD mice (D, F), whereas wild-type control brains (C, E) are completely devoid of plaques. GFAP immunohistochemistry (activated astrocytes, red in G) or GSA-lectin (activated microglia, red in H) in combination with thioflavin S staining (green in G and H) revealed plaques surrounded by reactive astrocytes and associated with activated microglia in 5XFAD mice. Scale bars: 500 µm (A–F), 250 µm (G, H), and 100 µm (inset in G and H).CC BY · PubMed Central
Figure 2 Progression of plaque formation with age in 5XFAD transgenic mice. The plaque density in the hippocampus (HC) and entorhinal cortex (EC) of male and female 5XFAD mice at various ages was determined using thioflavin S staining. 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.
Figure 2 Progression of plaque formation with age in 5XFAD transgenic mice. The plaque density in the hippocampus (HC) and entorhinal cortex (EC) of male and female 5XFAD mice at various ages was determined using thioflavin S staining. 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.CC BY · PubMed Central
Figure 3 Behavioral analysis of 7-month-old 5XFAD transgenic mice. 5XFAD mice (10 female, 8 male) were analyzed in a series of behavioral tests in comparison to non-transgenic littermates (6 female, 8 male). A significant reduction in body weight (A) of transgenic (white columns) compared to non-transgenic (black columns) mice was observed for both sexes. The grip strength (B) differed between sexes but not between transgenic and non-transgenic mice. Maximum grip strength (black, white columns) and average grip strength (grey, stippled columns) were similar for non-transgenic (black, grey columns) and transgenic mice (white, stippled columns). The rota-rod (C; black control females, grey control males, white transgenic females, dotted transgenic males) did not reveal differences between transgenic and control littermate mice. In the open field (D) transgenic mice (white columns) of both sexes stayed less time in the corners compared to their wild-type littermates (black columns). In the light-dark avoidance paradigm (E, F, G) transgenic mice (white columns) showed less transitions (E), stayed longer time in the light (F), and had a much greater latency to enter the dark compartment (G) both at the first encounter or tested for memory 3 weeks later (grey columns non-transgenic, stippled columns 5XFAD in G). In the O-Maze (H, I) 5XFAD mice (white columns) spend more time (H) and traveled longer distances (I) in the open areas compared to littermate controls (black columns). Fear conditioning (J) did not differ significantly between 5XFAD (white, stippled columns) and control littermate mice (black, grey columns) with respect to freezing in the same context (black, white columns) or when exposed to the tone in a novel environment (grey, stippled columns). Prepulse inhibition of the startle response (K) was not obtained in 5XFAD mice (squares) in contrast to wild-type littermates (diamonds) in both sexes (males open, females filled symbols).
Figure 3 Behavioral analysis of 7-month-old 5XFAD transgenic mice. 5XFAD mice (10 female, 8 male) were analyzed in a series of behavioral tests in comparison to non-transgenic littermates (6 female, 8 male). A significant reduction in body weight (A) of transgenic (white columns) compared to non-transgenic (black columns) mice was observed for both sexes. The grip strength (B) differed between sexes but not between transgenic and non-transgenic mice. Maximum grip strength (black, white columns) and average grip strength (grey, stippled columns) were similar for non-transgenic (black, grey columns) and transgenic mice (white, stippled columns). The rota-rod (C; black control females, grey control males, white transgenic females, dotted transgenic males) did not reveal differences between transgenic and control littermate mice. In the open field (D) transgenic mice (white columns) of both sexes stayed less time in the corners compared to their wild-type littermates (black columns). In the light-dark avoidance paradigm (E, F, G) transgenic mice (white columns) showed less transitions (E), stayed longer time in the light (F), and had a much greater latency to enter the dark compartment (G) both at the first encounter or tested for memory 3 weeks later (grey columns non-transgenic, stippled columns 5XFAD in G). In the O-Maze (H, I) 5XFAD mice (white columns) spend more time (H) and traveled longer distances (I) in the open areas compared to littermate controls (black columns). Fear conditioning (J) did not differ significantly between 5XFAD (white, stippled columns) and control littermate mice (black, grey columns) with respect to freezing in the same context (black, white columns) or when exposed to the tone in a novel environment (grey, stippled columns). Prepulse inhibition of the startle response (K) was not obtained in 5XFAD mice (squares) in contrast to wild-type littermates (diamonds) in both sexes (males open, females filled symbols).CC BY · PubMed Central
Figure 4 Water consumption, galantamine uptake, and body weight of 5XFAD-transgenic mice treated with galantamine. Water consumption (A) of 5XFAD transgenic was similar irrespective of added galantamine (black triangles: water (n = 16); diamonds: high dose (n = 16), squares: low dose (n = 8). Galantamine uptake (B) was calculated from the amount of drinking water consumed for the low dose (squares, 12 then 60 mg/l) and the high dose (diamonds, 36 then 120 mg/l). The body weight (C) of non-transgenic control (black) or 5XFAD (white) mice was not significantly influenced by the treatment and the behavioral tests.
Figure 4 Water consumption, galantamine uptake, and body weight of 5XFAD-transgenic mice treated with galantamine. Water consumption (A) of 5XFAD transgenic was similar irrespective of added galantamine (black triangles: water (n = 16); diamonds: high dose (n = 16), squares: low dose (n = 8). Galantamine uptake (B) was calculated from the amount of drinking water consumed for the low dose (squares, 12 then 60 mg/l) and the high dose (diamonds, 36 then 120 mg/l). The body weight (C) of non-transgenic control (black) or 5XFAD (white) mice was not significantly influenced by the treatment and the behavioral tests.CC BY · PubMed Central
Figure 5 Behavioral analysis of 5XFAD-transgenic mice after treatment with galantamine. In the Open Field (A, B) galantamine treatment restored the preference for the corners (A) and the avoidance of the center (B). Non-transgenic mice receiving water (black columns) showed a significantly higher corner preference (**, p = 0.0045) and avoidance of the center (**, p = 0.0048) compared to untreated 5XFAD transgenic mice (white columns). Treatment of 5XFAD transgenic mice with low dose (stippled columns) or high dose (hatched columns) galantamine increased their corner preference and center avoidance in a dose dependent manner. High dose treated transgenic mice spend significantly (**, p = 0.002) more time in the corners compared to untreated transgenic mice or low dose treated mice (*, p = 0.0451). Non-transgenic mice receiving high dose galantamine (grey columns). In the light-dark avoidance paradigm (C, D), high dose galantamine treatment of 5XFAD transgenic mice (hatched columns) reduced the time in the light (C) to untreated non-transgenic (black columns) control levels. In contrast, the number of transitions (D) is even further reduced by galantamine treatment of 5XFAD transgenic mice (*, p<0.005). The magnitude of the startle response (E) was not affected by galantamine treatment of 5XFAD transgenic mice. During fear conditioning (F, G), galantamine increased the context memory (F) and the tone memory (G) of non-transgenic and 5XFAD transgenic mice similarly.
Figure 5 Behavioral analysis of 5XFAD-transgenic mice after treatment with galantamine. In the Open Field (A, B) galantamine treatment restored the preference for the corners (A) and the avoidance of the center (B). Non-transgenic mice receiving water (black columns) showed a significantly higher corner preference (**, p = 0.0045) and avoidance of the center (**, p = 0.0048) compared to untreated 5XFAD transgenic mice (white columns). Treatment of 5XFAD transgenic mice with low dose (stippled columns) or high dose (hatched columns) galantamine increased their corner preference and center avoidance in a dose dependent manner. High dose treated transgenic mice spend significantly (**, p = 0.002) more time in the corners compared to untreated transgenic mice or low dose treated mice (*, p = 0.0451). Non-transgenic mice receiving high dose galantamine (grey columns). In the light-dark avoidance paradigm (C, D), high dose galantamine treatment of 5XFAD transgenic mice (hatched columns) reduced the time in the light (C) to untreated non-transgenic (black columns) control levels. In contrast, the number of transitions (D) is even further reduced by galantamine treatment of 5XFAD transgenic mice (*, p<0.005). The magnitude of the startle response (E) was not affected by galantamine treatment of 5XFAD transgenic mice. During fear conditioning (F, G), galantamine increased the context memory (F) and the tone memory (G) of non-transgenic and 5XFAD transgenic mice similarly.CC BY · PubMed Central
Figure 6 Quantification of plaque density after galantamine treatment. The plaque density in the hippocampus (A) of high dose galantamine treated female (black column, n = 22 sections) and male (white column, n = 47) 5XFAD transgenic mice is significantly reduced in comparison to littermate untreated 5XFAD transgenic mice (female grey column, n = 28; male stippled, n = 50) (***, p<0.0001). The reduction after treatment is even stronger for the entorhinal cortex (B) (treated female black column, n = 27, and male white column, n = 59) (untreated female grey column, n = 45, and male stippled column, n = 59). Astrocyte density and plaque density are strongly correlated in 5XFAD transgenic mice (C) (R2 = 0.62; ANOVA F(1,21) = 34.232; p<0.0001).
Figure 6 Quantification of plaque density after galantamine treatment. The plaque density in the hippocampus (A) of high dose galantamine treated female (black column, n = 22 sections) and male (white column, n = 47) 5XFAD transgenic mice is significantly reduced in comparison to littermate untreated 5XFAD transgenic mice (female grey column, n = 28; male stippled, n = 50) (***, p<0.0001). The reduction after treatment is even stronger for the entorhinal cortex (B) (treated female black column, n = 27, and male white column, n = 59) (untreated female grey column, n = 45, and male stippled column, n = 59). Astrocyte density and plaque density are strongly correlated in 5XFAD transgenic mice (C) (R2 = 0.62; ANOVA F(1,21) = 34.232; p<0.0001).CC BY · PubMed Central
Figure 7 Plaque density after galantamine treatment. Thioflavin S staining of representative coronal brain sections from untreated (A, C, E, G) in comparison to chronically high dose galantamine treated (B, D, F, H) 22-week-old 5XFAD transgenic littermate mice. Fewer plaques are detected in treated animals. Males (A–D) show fewer plaques in comparison to females (E–H), both, in the entorhinal cortex (A, B, E, F) and in the hippocampus (C, D, G, H). Scale bars 500 µm.
Figure 7 Plaque density after galantamine treatment. Thioflavin S staining of representative coronal brain sections from untreated (A, C, E, G) in comparison to chronically high dose galantamine treated (B, D, F, H) 22-week-old 5XFAD transgenic littermate mice. Fewer plaques are detected in treated animals. Males (A–D) show fewer plaques in comparison to females (E–H), both, in the entorhinal cortex (A, B, E, F) and in the hippocampus (C, D, G, H). Scale bars 500 µm.CC BY · PubMed Central

Verification

Claims the paper makes

67 Own result · 40 Not checked yet · 17 Own interpretation · 4 Own method · 3 No basis given

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  • Probably not a substantial claim. 34
  • It may state two separate claims as one. 17
  • The quote only partly states this claim. 7
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

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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

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Citations

Cites

Show all 63 references

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

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Metadata

Authors
Bhattacharya, S., Haertel, C., Maelicke, A., & Montag, D.
Affiliations
Leibniz Institute for Neurobiology (DE)
Corresponding author
Montag, Dirk
Venue
PLoS ONE
Published
2014-02-21
Volume
9
Issue
2
Pages
e89454
ISSN
1932-6203 (ISSN-L)
OpenAlex
W2037958764
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
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
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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

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