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Maternal separation differentially modulates early pathology by sex in 5xFAD Alzheimer’s disease-transgenic mice

Garcia, M.g. LU orcid ; Paulus, A. LU ; Vázquez-Reyes, S. ; Klementieva, O. LU orcid ; Gouras, G.k. LU orcid ; Bachiller, S. LU and Deierborg, T. LU (2023) In Brain, Behavior, & Immunity - Health 32.
Abstract
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,... (More)
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. (Less)
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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, Amyloid-β, Early-life stress, Maternal separation, Neuroinflammation
in
Brain, Behavior, & Immunity - Health
volume
32
article number
100663
pages
10 pages
publisher
Elsevier
external identifiers
  • pmid:37503358
  • scopus:85166947847
ISSN
2666-3546
DOI
10.1016/j.bbih.2023.100663
project
Neuroinflammation and amyloid-β in early Alzheimer’s disease: Insight into the earliest events using mouse models
language
English
LU publication?
yes
id
a5309640-03a5-4120-bf31-0d11524d58f8
date added to LUP
2023-08-02 19:29:34
date last changed
2024-02-14 13:51:02
@article{a5309640-03a5-4120-bf31-0d11524d58f8,
  abstract     = {{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.}},
  author       = {{Garcia, M.g. and Paulus, A. and Vázquez-Reyes, S. and Klementieva, O. and Gouras, G.k. and Bachiller, S. and Deierborg, T.}},
  issn         = {{2666-3546}},
  keywords     = {{Alzheimer's disease; Amyloid-β; Early-life stress; Maternal separation; Neuroinflammation}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Brain, Behavior, & Immunity - Health}},
  title        = {{Maternal separation differentially modulates early pathology by sex in 5xFAD Alzheimer’s disease-transgenic mice}},
  url          = {{http://dx.doi.org/10.1016/j.bbih.2023.100663}},
  doi          = {{10.1016/j.bbih.2023.100663}},
  volume       = {{32}},
  year         = {{2023}},
}