Sex Differences in Metabolic Indices and Chronic Neuroinflammation in Response to Prolonged High-Fat Diet in ApoE4 Knock-In Mice
Late-onset Alzheimer’s disease (LOAD) likely results from combinations of risk factors that include both genetic predisposition and modifiable lifestyle factors. The E4 allele of apolipoprotein E (ApoE) is the most significant genetic risk factor for LOAD. A Western-pattern diet (WD) has been shown...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/7/3921 |
| _version_ | 1797438943585632256 |
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| author | Jennifer M. Mattar Mark Majchrzak Jaclyn Iannucci Sydney Bartman John K. Robinson Paula Grammas |
| author_facet | Jennifer M. Mattar Mark Majchrzak Jaclyn Iannucci Sydney Bartman John K. Robinson Paula Grammas |
| author_sort | Jennifer M. Mattar |
| collection | DOAJ |
| description | Late-onset Alzheimer’s disease (LOAD) likely results from combinations of risk factors that include both genetic predisposition and modifiable lifestyle factors. The E4 allele of apolipoprotein E (ApoE) is the most significant genetic risk factor for LOAD. A Western-pattern diet (WD) has been shown to strongly increase the risk of cardiovascular disease and diabetes, conditions which have been strongly linked to an increased risk for developing AD. Little is known about how the WD may contribute to, or enhance, the increased risk presented by possession of the ApoE4 allele. To model this interaction over the course of a lifetime, we exposed male and female homozygote ApoE4 knock-in mice and wild-type controls to nine months of a high-fat WD or standard chow diet. At eleven months of age, the mice were tested for glucose tolerance and then for general activity and spatial learning and memory. Postmortem analysis of liver function and neuroinflammation in the brain was also assessed. Our results suggest that behavior impairments resulted from the convergence of interacting metabolic alterations, made worse in a male ApoE4 mice group who also showed liver dysfunction, leading to a higher level of inflammatory cytokines in the brain. Interestingly, female ApoE4 mice on a WD revealed impairments in spatial learning and memory without the observed liver dysfunction or increase in inflammatory markers in the brain. These results suggest multiple direct and indirect pathways through which ApoE and diet-related factors interact. The striking sex difference in markers of chronic neuroinflammation in male ApoE4 mice fed the high-fat WD suggests a specific mechanism of interaction conferring significant enhanced LOAD risk for humans with the ApoE4 allele, which may differ between sexes. Additionally, our results suggest researchers exercise caution when designing and interpreting results of experiments employing a WD, being careful not to assume a WD impacts both sexes by the same mechanisms. |
| first_indexed | 2024-03-09T11:45:37Z |
| format | Article |
| id | doaj.art-8e41a018c1374826a6e81cca553f16c5 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T11:45:37Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-8e41a018c1374826a6e81cca553f16c52023-11-30T23:24:03ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-04-01237392110.3390/ijms23073921Sex Differences in Metabolic Indices and Chronic Neuroinflammation in Response to Prolonged High-Fat Diet in ApoE4 Knock-In MiceJennifer M. Mattar0Mark Majchrzak1Jaclyn Iannucci2Sydney Bartman3John K. Robinson4Paula Grammas5Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI 02881, USAGeorge & Anne Ryan Institute for Neuroscience, University of Rhode Island, 130 Flagg Rd, Kingston, RI 02881, USAInterdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI 02881, USAInterdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI 02881, USAInterdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI 02881, USAGeorge & Anne Ryan Institute for Neuroscience, University of Rhode Island, 130 Flagg Rd, Kingston, RI 02881, USALate-onset Alzheimer’s disease (LOAD) likely results from combinations of risk factors that include both genetic predisposition and modifiable lifestyle factors. The E4 allele of apolipoprotein E (ApoE) is the most significant genetic risk factor for LOAD. A Western-pattern diet (WD) has been shown to strongly increase the risk of cardiovascular disease and diabetes, conditions which have been strongly linked to an increased risk for developing AD. Little is known about how the WD may contribute to, or enhance, the increased risk presented by possession of the ApoE4 allele. To model this interaction over the course of a lifetime, we exposed male and female homozygote ApoE4 knock-in mice and wild-type controls to nine months of a high-fat WD or standard chow diet. At eleven months of age, the mice were tested for glucose tolerance and then for general activity and spatial learning and memory. Postmortem analysis of liver function and neuroinflammation in the brain was also assessed. Our results suggest that behavior impairments resulted from the convergence of interacting metabolic alterations, made worse in a male ApoE4 mice group who also showed liver dysfunction, leading to a higher level of inflammatory cytokines in the brain. Interestingly, female ApoE4 mice on a WD revealed impairments in spatial learning and memory without the observed liver dysfunction or increase in inflammatory markers in the brain. These results suggest multiple direct and indirect pathways through which ApoE and diet-related factors interact. The striking sex difference in markers of chronic neuroinflammation in male ApoE4 mice fed the high-fat WD suggests a specific mechanism of interaction conferring significant enhanced LOAD risk for humans with the ApoE4 allele, which may differ between sexes. Additionally, our results suggest researchers exercise caution when designing and interpreting results of experiments employing a WD, being careful not to assume a WD impacts both sexes by the same mechanisms.https://www.mdpi.com/1422-0067/23/7/3921late-onset Alzheimer’s diseaseWestern-pattern dietmemoryliverneuroinflammationdiabetes |
| spellingShingle | Jennifer M. Mattar Mark Majchrzak Jaclyn Iannucci Sydney Bartman John K. Robinson Paula Grammas Sex Differences in Metabolic Indices and Chronic Neuroinflammation in Response to Prolonged High-Fat Diet in ApoE4 Knock-In Mice International Journal of Molecular Sciences late-onset Alzheimer’s disease Western-pattern diet memory liver neuroinflammation diabetes |
| title | Sex Differences in Metabolic Indices and Chronic Neuroinflammation in Response to Prolonged High-Fat Diet in ApoE4 Knock-In Mice |
| title_full | Sex Differences in Metabolic Indices and Chronic Neuroinflammation in Response to Prolonged High-Fat Diet in ApoE4 Knock-In Mice |
| title_fullStr | Sex Differences in Metabolic Indices and Chronic Neuroinflammation in Response to Prolonged High-Fat Diet in ApoE4 Knock-In Mice |
| title_full_unstemmed | Sex Differences in Metabolic Indices and Chronic Neuroinflammation in Response to Prolonged High-Fat Diet in ApoE4 Knock-In Mice |
| title_short | Sex Differences in Metabolic Indices and Chronic Neuroinflammation in Response to Prolonged High-Fat Diet in ApoE4 Knock-In Mice |
| title_sort | sex differences in metabolic indices and chronic neuroinflammation in response to prolonged high fat diet in apoe4 knock in mice |
| topic | late-onset Alzheimer’s disease Western-pattern diet memory liver neuroinflammation diabetes |
| url | https://www.mdpi.com/1422-0067/23/7/3921 |
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