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Cited by 232Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeurological Disease Mechanisms and Treatments

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High-fat diet-induced memory impairment in triple-transgenic Alzheimer’s disease (3xTgAD) mice is independent of changes in amyloid and tau pathology.

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Knight, Elysse M., Martins, Isaura V.A., Gümüsgöz, Sarah, Allan, Stuart M., Lawrence, Catherine B.·2014·Neurobiology of Aging
DOI 10.1016/j.neurobiolaging.2014.02.010PMC PMC4024197
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Abstract

Obesity and consumption of a high-fat diet are known to increase the risk of Alzheimer's disease (AD). Diets high in fat also increase disease neuropathology and/or cognitive deficits in AD mouse models. However, the effect of a high-fat diet on both the neuropathology and memory impairments in the triple-transgenic mouse model of AD (3xTgAD) is unknown. Therefore, groups of 2-month-old male 3xTgAD and control (non-Tg) mice were maintained on a high-fat or control diet and memory was assessed at the age of 3-4, 7-8, 11-12, and 15-16 months using a series of behavioral tests. A comparable increase in body weight was observed in non-Tg and 3xTgAD mice after high-fat feeding at all ages tested but a significantly greater increase in epididymal adipose tissue was observed in 3xTgAD mice at the age of 7-8, 11-12, and 15-16 months. A high-fat diet caused memory impairments in non-Tg control mice as early as the age of 3-4 months. In 3xTgAD mice, high-fat consumption led to a reduction in the age of onset and an increase in the extent of memory impairments. Some of these effects of high-fat diet on cognition in non-Tg and 3xTgAD mice were transient, and the age at which cognitive impairment was detected depended on the behavioral test. The effect of high-fat diet on memory in the 3xTgAD mice was independent of changes in AD neuropathology as no significant differences in (plaques, oligomers) or tau neuropathology were observed. An acute increase in microglial activation was seen in high-fat fed 3xTgAD mice at the age of 3-4 months but in non-Tg control mice microglial activation was not observed until the age of 15-16 months. These data indicate therefore that a high-fat diet has rapid and long-lasting negative effects on memory in both control and AD mice that are associated with neuroinflammation, but independent of changes in beta amyloid and tau neuropathology in the AD mice.

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Fig. 1 Body weight of 3xTgAD and non-Tg mice in response to a high-fat diet. Male 3xTgAD and non-Tg control mice were maintained on either a control or high-fat diet from the age of 8 weeks (at the age of 2 months) and body weight was assessed in separate groups of mice at the age of 3–4 (A), 7–8 (B), 11–12 (C), and 15–16 (D) months. Data are means ± SEM, n = 6–12/group. * p < 0.05, ** p < 0.01, *** p < 0.001 non-Tg versus 3xTgAD mice on control diet; ##p < 0.01, ###p < 0.001 non-Tg versus 3xTgAD mice on high-fat diet; $p < 0.05, $$p < 0.01, $$$p < 0.001 non-Tg on a control versus high-fat diet; &p < 0.05, &&p < 0.01, &&&p <0.001 3xTgAD on a control versus high-fat diet. Three-way repeated measures ANOVAs with Scheffe post hoc analysis. Abbreviations: ANOVA, analysis of variance; SEM, standard error of the mean.
Fig. 1 Body weight of 3xTgAD and non-Tg mice in response to a high-fat diet. Male 3xTgAD and non-Tg control mice were maintained on either a control or high-fat diet from the age of 8 weeks (at the age of 2 months) and body weight was assessed in separate groups of mice at the age of 3–4 (A), 7–8 (B), 11–12 (C), and 15–16 (D) months. Data are means ± SEM, n = 6–12/group. * p < 0.05, ** p < 0.01, *** p < 0.001 non-Tg versus 3xTgAD mice on control diet; ##p < 0.01, ###p < 0.001 non-Tg versus 3xTgAD mice on high-fat diet; $p < 0.05, $$p < 0.01, $$$p < 0.001 non-Tg on a control versus high-fat diet; &p < 0.05, &&p < 0.01, &&&p <0.001 3xTgAD on a control versus high-fat diet. Three-way repeated measures ANOVAs with Scheffe post hoc analysis. Abbreviations: ANOVA, analysis of variance; SEM, standard error of the mean.CC BY · PubMed Central
Fig. 2 High-fat diet impairs learning in the Y-maze spontaneous alternation test in 3xTgAD and non-Tg mice. Male 3xTgAD and non-Tg control mice were maintained on either a control or high-fat diet from the age of 8 weeks. Cognitive function was assessed in the Y-maze spontaneous alternation test in separate groups of mice at the age of 3–4 (A), 7–8 (B), 11–12 (C), and 15–16 (D) months. Data are means ± SEM. n = 6–12/group. * p < 0.05, ** p < 0.01, *** p < 0.001 versus non-Tg mice on the same diet, ##p < 0.01, ###p < 0.001 versus control-fed mice of the same genotype. Two-way ANOVA with Bonferroni post hoc analysis. Abbreviations: ANOVA, analysis of variance; SEM, standard error of the mean.
Fig. 2 High-fat diet impairs learning in the Y-maze spontaneous alternation test in 3xTgAD and non-Tg mice. Male 3xTgAD and non-Tg control mice were maintained on either a control or high-fat diet from the age of 8 weeks. Cognitive function was assessed in the Y-maze spontaneous alternation test in separate groups of mice at the age of 3–4 (A), 7–8 (B), 11–12 (C), and 15–16 (D) months. Data are means ± SEM. n = 6–12/group. * p < 0.05, ** p < 0.01, *** p < 0.001 versus non-Tg mice on the same diet, ##p < 0.01, ###p < 0.001 versus control-fed mice of the same genotype. Two-way ANOVA with Bonferroni post hoc analysis. Abbreviations: ANOVA, analysis of variance; SEM, standard error of the mean.CC BY · PubMed Central
Fig. 3 High-fat diet impairs learning in the smell recognition test in 3xTgAD and non-Tg mice. Male 3xTgAD and non-Tg control mice were maintained on either a control or high-fat diet from the age of 8 weeks. Cognitive function was assessed in the smell recognition test in separate groups of mice at the age of 3–4 (A), 7–8 (B), 11–12 (C), and 15–16 (D) months. During phase 1, the mice were placed in an arena for 10 minutes with 2 identically scented balls (data not shown). During phase 2, after an interval of 3 minutes, the mice were placed back into the arena with one familiar scented ball (presented in phase 1) and one novel scented ball for 4 minutes and percentage time exploring balls was compared. Data are means ± SEM. n = 6–12/group. * p < 0.05, ** p < 0.01 for novel versus familiar smell; Student t test. Abbreviation: SEM, standard error of the mean.
Fig. 3 High-fat diet impairs learning in the smell recognition test in 3xTgAD and non-Tg mice. Male 3xTgAD and non-Tg control mice were maintained on either a control or high-fat diet from the age of 8 weeks. Cognitive function was assessed in the smell recognition test in separate groups of mice at the age of 3–4 (A), 7–8 (B), 11–12 (C), and 15–16 (D) months. During phase 1, the mice were placed in an arena for 10 minutes with 2 identically scented balls (data not shown). During phase 2, after an interval of 3 minutes, the mice were placed back into the arena with one familiar scented ball (presented in phase 1) and one novel scented ball for 4 minutes and percentage time exploring balls was compared. Data are means ± SEM. n = 6–12/group. * p < 0.05, ** p < 0.01 for novel versus familiar smell; Student t test. Abbreviation: SEM, standard error of the mean.CC BY · PubMed Central
Fig. 4 High-fat diet impairs learning in the novel object recognition test in non-Tg mice. Male 3xTgAD and non-Tg control mice were maintained on either a control or high-fat diet from the age of 8 weeks. Cognitive function was assessed in the novel object recognition test in separate groups of mice at the age of 3–4 (A), 7–8 (B), 11–12 (C), and 15–16 (D) months. During phase 1, the mice were placed in an arena for 10 minutes with 2 identical novel objects (data not shown). During phase 2, after an interval of 1 hour, the mice were placed back into the arena with one familiar object (presented in phase 1) and one novel object for 4 minutes and percentage time exploring objects was compared. Data are means ± SEM. n = 6–12/group. * p < 0.05, ** p < 0.01, *** p < 0.01 for novel versus familiar object; Student t test. Abbreviation: SEM, standard error of the mean.
Fig. 4 High-fat diet impairs learning in the novel object recognition test in non-Tg mice. Male 3xTgAD and non-Tg control mice were maintained on either a control or high-fat diet from the age of 8 weeks. Cognitive function was assessed in the novel object recognition test in separate groups of mice at the age of 3–4 (A), 7–8 (B), 11–12 (C), and 15–16 (D) months. During phase 1, the mice were placed in an arena for 10 minutes with 2 identical novel objects (data not shown). During phase 2, after an interval of 1 hour, the mice were placed back into the arena with one familiar object (presented in phase 1) and one novel object for 4 minutes and percentage time exploring objects was compared. Data are means ± SEM. n = 6–12/group. * p < 0.05, ** p < 0.01, *** p < 0.01 for novel versus familiar object; Student t test. Abbreviation: SEM, standard error of the mean.CC BY · PubMed Central
Fig. 5 High-fat diet impairs learning in the Morris water maze in 3xTgAD and non-Tg mice. Male 3xTgAD and non-Tg control mice were maintained on either a control or high-fat diet from the age of 8 weeks. Cognitive function was assessed in the Morris water maze in separate groups of mice at the age of 3–4 (A), 7–8 (B), 11–12 (C), and 15–16 (D) months. Mice were given 4 trials a day for 8 days of submerged platform training in the MWM (A–D). Twenty-four hours after the final trial the mice were given a probe test with no platform (E–H). Data are mean +/− SEM. For escape latency, * p < 0.05, ** p < 0.01, *** p < 0.001 day 1 versus days 2–8. For percentage time in target, * p < 0.05, ** p < 0.01, *** p <0.001 versus non-Tg mice on the same diet, #p < 0.05, ##p < 0.01 versus control-fed mice of the same genotype. Abbreviations: MWM, Morris water maze; SEM, standard error of the mean.
Fig. 5 High-fat diet impairs learning in the Morris water maze in 3xTgAD and non-Tg mice. Male 3xTgAD and non-Tg control mice were maintained on either a control or high-fat diet from the age of 8 weeks. Cognitive function was assessed in the Morris water maze in separate groups of mice at the age of 3–4 (A), 7–8 (B), 11–12 (C), and 15–16 (D) months. Mice were given 4 trials a day for 8 days of submerged platform training in the MWM (A–D). Twenty-four hours after the final trial the mice were given a probe test with no platform (E–H). Data are mean +/− SEM. For escape latency, * p < 0.05, ** p < 0.01, *** p < 0.001 day 1 versus days 2–8. For percentage time in target, * p < 0.05, ** p < 0.01, *** p <0.001 versus non-Tg mice on the same diet, #p < 0.05, ##p < 0.01 versus control-fed mice of the same genotype. Abbreviations: MWM, Morris water maze; SEM, standard error of the mean.CC BY · PubMed Central
Fig. 6 High-fat diet has no effect on Aβ or tau neuropathology in the hippocampus of 3xTgAD mice. Male 3xTgAD and non-Tg control mice were maintained on either a control or high-fat diet from the age of 8 weeks until the age of 11–12 and 15–16 months. Immunohistochemistry for Aβ (A) or hyperphosphorylated tau (B) was performed using 6E10 and AT8 antibodies, respectively. Representative sections for 3xTgAD mice are shown for the hippocampus indicating the extracellular Aβ plaque burden and tau-positive neurons. Quantification is presented in Table 2. Scale bars 200 μm. Abbreviation: Aβ, beta amyloid.
Fig. 6 High-fat diet has no effect on Aβ or tau neuropathology in the hippocampus of 3xTgAD mice. Male 3xTgAD and non-Tg control mice were maintained on either a control or high-fat diet from the age of 8 weeks until the age of 11–12 and 15–16 months. Immunohistochemistry for Aβ (A) or hyperphosphorylated tau (B) was performed using 6E10 and AT8 antibodies, respectively. Representative sections for 3xTgAD mice are shown for the hippocampus indicating the extracellular Aβ plaque burden and tau-positive neurons. Quantification is presented in Table 2. Scale bars 200 μm. Abbreviation: Aβ, beta amyloid.CC BY · PubMed Central
Fig. 7 High-fat diet increases microglia activation in the hippocampus of 3xTgAD and non-Tg mice. Male 3xTgAD and non-Tg control mice were maintained on either a control or high-fat diet from the age of 8 weeks until the age of 3–4 (A), 7–8 (B), 11–12 (C), and 15–16 (D) months. Microglia activation were identified by increased Iba1 immunopositivity, enlarged and/or irregular cell bodies, thickened, partial or complete loss of processes and were seen after high-fat feeding in 3xTgAD mice at the age of 3–4 months and non-Tg mice at the age of 15–16 months. An increase in microglia activation was also observed in control fed 3xTgAD mice over time. (E) Representative photomicrographs in the hippocampus from 3–4 and 15 to 16-month-old mice. Scale bars 200 μm and 25 μm (insets). * p < 0.05, ** p < 0.01, *** p < 0.001 versus non-Tg group on the same diet; #p < 0.05 versus control fed of the same genotype.
Fig. 7 High-fat diet increases microglia activation in the hippocampus of 3xTgAD and non-Tg mice. Male 3xTgAD and non-Tg control mice were maintained on either a control or high-fat diet from the age of 8 weeks until the age of 3–4 (A), 7–8 (B), 11–12 (C), and 15–16 (D) months. Microglia activation were identified by increased Iba1 immunopositivity, enlarged and/or irregular cell bodies, thickened, partial or complete loss of processes and were seen after high-fat feeding in 3xTgAD mice at the age of 3–4 months and non-Tg mice at the age of 15–16 months. An increase in microglia activation was also observed in control fed 3xTgAD mice over time. (E) Representative photomicrographs in the hippocampus from 3–4 and 15 to 16-month-old mice. Scale bars 200 μm and 25 μm (insets). * p < 0.05, ** p < 0.01, *** p < 0.001 versus non-Tg group on the same diet; #p < 0.05 versus control fed of the same genotype.CC BY · PubMed Central

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Metadata

Authors
Knight, E. M., Martins, I. V. A., Gümüsgöz, S., Allan, S. M., & Lawrence, C. B.
Affiliations
University of Manchester (GB)
Corresponding author
Lawrence, Catherine B.
ORCID
Venue
Neurobiology of Aging
Publisher
Elsevier BV
Published
2014-08
Volume
35
Issue
8
Pages
1821-1832
ISSN
0197-4580 (ISSN-L)
DOI
10.1016/j.neurobiolaging.2014.02.010
PMC
PMC4024197
OpenAlex
W1994083528
Cited by
232
References
56
Citations by year
2026: 11 · 2025: 14 · 2024: 14 · 2023: 19 · 2022: 23 · 2021: 20 · 2020: 21 · 2019: 26 · 2018: 24 · 2017: 18 · 2016: 30 · 2015: 7 · 2014: 5
FWCI
13.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Aging (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
Funders
Medical Research Council
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
high-fat diet, Alzheimer's disease, 3xTg-AD mice, memory impairment, obesity, amyloid plaques, tau pathology, microglial activation, neuroinflammation, adipose tissue, cognitive aging
MeSH terms
Adipose Tissue, Alzheimer Disease, Animals, Brain, Cognition, Disease Models, Animal, Epididymis, Male, Memory, Mice, Transgenic, Risk, Amyloid beta-Peptides, tau Proteins, Mice, Diet, High-Fat

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