Maternal separation differentially modulates early pathology by sex in 5xFAD Alzheimer’s disease-transgenic mice
Alzheimer’s disease (AD) is the most common neurodegenerative disease. Most cases of AD are considered idiopathic and likely due to a combination of genetic, environmental, and lifestyle-related risk factors. Despite occurring decades before the typical age of an AD diagnosis, early-life stress (ELS...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-10-01
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| Series: | Brain, Behavior, & Immunity - Health |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666354623000777 |
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| author | M.G. Garcia A. Paulus S. Vázquez-Reyes O. Klementieva G.K. Gouras S. Bachiller T. Deierborg |
| author_facet | M.G. Garcia A. Paulus S. Vázquez-Reyes O. Klementieva G.K. Gouras S. Bachiller T. Deierborg |
| author_sort | M.G. Garcia |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is the most common neurodegenerative disease. Most cases of AD are considered idiopathic and likely due to a combination of genetic, environmental, and lifestyle-related risk factors. Despite occurring decades before the typical age of an AD diagnosis, early-life stress (ELS) has been suggested to have long-lasting effects that may contribute to AD risk and pathogenesis. Still, the mechanisms that underlie the role of ELS on AD risk remain largely unknown. Here, we used 5xFAD transgenic mice to study relatively short-term alterations related to ELS in an AD-like susceptible mouse model at 6 weeks of age. To model ELS, we separated pups from their dams for 3 h per day from postnatal day 2–14. Around 6 weeks of age, we found that maternally separated (MS) 5xFAD mice, particularly female mice, displayed increased amyloid-β-immunoreactivity in the anterior cingulate cortex (ACC) and basolateral amygdala (BLA). In anterior cingulate cortex, we also noted significantly increased intraneuronal amyloid-β-immunoreactivity associated with MS but only in female mice. Moreover, IBA1-positive DAPI density was significantly increased in relation to MS in ACC and BLA, and microglia in BLA of MS mice had significantly different morphology compared to microglia in non-MS 5xFAD mice. Cytokine analysis showed that male MS mice, specifically, had increased levels of neuroinflammatory markers CXCL1 and IL-10 in hippocampal extracts compared to non-MS counterparts. Additionally, hippocampal extracts from both male and female MS 5xFAD mice had decreased levels of synapse- and activity-related markers Bdnf, 5htr6, Cox2, and Syp in hippocampus. Lastly, we performed behavioral tests to evaluate anxiety- and depressive-like behavior and working memory but could not detect any significant differences between groups. Overall, we detected several sex-specific molecular and cellular alterations in 6-week-old adolescent 5xFAD mice associated with MS that may help explain the connection between ELS and AD risk. |
| first_indexed | 2024-03-12T11:35:14Z |
| format | Article |
| id | doaj.art-27c6b826b98642398251c01e6e5d776d |
| institution | Directory Open Access Journal |
| issn | 2666-3546 |
| language | English |
| last_indexed | 2024-03-12T11:35:14Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
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| series | Brain, Behavior, & Immunity - Health |
| spelling | doaj.art-27c6b826b98642398251c01e6e5d776d2023-09-01T05:03:11ZengElsevierBrain, Behavior, & Immunity - Health2666-35462023-10-0132100663Maternal separation differentially modulates early pathology by sex in 5xFAD Alzheimer’s disease-transgenic miceM.G. Garcia0A. Paulus1S. Vázquez-Reyes2O. Klementieva3G.K. Gouras4S. Bachiller5T. Deierborg6Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden; Experimental Dementia Research Unit, Department of Experimental Medical Science, Lund University, 22184 Lund, SwedenExperimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden; Medical Microspectroscopy, Department of Experimental Medical Science, Lund University, 22184 Lund, SwedenExperimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, 22184 Lund, SwedenMedical Microspectroscopy, Department of Experimental Medical Science, Lund University, 22184 Lund, SwedenExperimental Dementia Research Unit, Department of Experimental Medical Science, Lund University, 22184 Lund, SwedenExperimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden; Institute of Biomedicine of Seville, IBiS/Virgen del Rocío University Hospital/CSIC/University of Seville/Seville, Spain; Department of Medical Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Seville, Seville, Spain; Corresponding author. Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, 22184 Lund, SwedenExperimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden; Corresponding authorExperimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, 22184 Lund, SwedenAlzheimer’s disease (AD) is the most common neurodegenerative disease. Most cases of AD are considered idiopathic and likely due to a combination of genetic, environmental, and lifestyle-related risk factors. Despite occurring decades before the typical age of an AD diagnosis, early-life stress (ELS) has been suggested to have long-lasting effects that may contribute to AD risk and pathogenesis. Still, the mechanisms that underlie the role of ELS on AD risk remain largely unknown. Here, we used 5xFAD transgenic mice to study relatively short-term alterations related to ELS in an AD-like susceptible mouse model at 6 weeks of age. To model ELS, we separated pups from their dams for 3 h per day from postnatal day 2–14. Around 6 weeks of age, we found that maternally separated (MS) 5xFAD mice, particularly female mice, displayed increased amyloid-β-immunoreactivity in the anterior cingulate cortex (ACC) and basolateral amygdala (BLA). In anterior cingulate cortex, we also noted significantly increased intraneuronal amyloid-β-immunoreactivity associated with MS but only in female mice. Moreover, IBA1-positive DAPI density was significantly increased in relation to MS in ACC and BLA, and microglia in BLA of MS mice had significantly different morphology compared to microglia in non-MS 5xFAD mice. Cytokine analysis showed that male MS mice, specifically, had increased levels of neuroinflammatory markers CXCL1 and IL-10 in hippocampal extracts compared to non-MS counterparts. Additionally, hippocampal extracts from both male and female MS 5xFAD mice had decreased levels of synapse- and activity-related markers Bdnf, 5htr6, Cox2, and Syp in hippocampus. Lastly, we performed behavioral tests to evaluate anxiety- and depressive-like behavior and working memory but could not detect any significant differences between groups. Overall, we detected several sex-specific molecular and cellular alterations in 6-week-old adolescent 5xFAD mice associated with MS that may help explain the connection between ELS and AD risk.http://www.sciencedirect.com/science/article/pii/S2666354623000777Alzheimer’s diseaseEarly-life stressMaternal separationNeuroinflammationAmyloid-β |
| spellingShingle | M.G. Garcia A. Paulus S. Vázquez-Reyes O. Klementieva G.K. Gouras S. Bachiller T. Deierborg Maternal separation differentially modulates early pathology by sex in 5xFAD Alzheimer’s disease-transgenic mice Brain, Behavior, & Immunity - Health Alzheimer’s disease Early-life stress Maternal separation Neuroinflammation Amyloid-β |
| title | Maternal separation differentially modulates early pathology by sex in 5xFAD Alzheimer’s disease-transgenic mice |
| title_full | Maternal separation differentially modulates early pathology by sex in 5xFAD Alzheimer’s disease-transgenic mice |
| title_fullStr | Maternal separation differentially modulates early pathology by sex in 5xFAD Alzheimer’s disease-transgenic mice |
| title_full_unstemmed | Maternal separation differentially modulates early pathology by sex in 5xFAD Alzheimer’s disease-transgenic mice |
| title_short | Maternal separation differentially modulates early pathology by sex in 5xFAD Alzheimer’s disease-transgenic mice |
| title_sort | maternal separation differentially modulates early pathology by sex in 5xfad alzheimer s disease transgenic mice |
| topic | Alzheimer’s disease Early-life stress Maternal separation Neuroinflammation Amyloid-β |
| url | http://www.sciencedirect.com/science/article/pii/S2666354623000777 |
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