Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging

Colleen A. Mangold, Benjamin Wronowski, Mei Du, Dustin R. Masser, Niran Hadad, Georgina V. Bixler, Robert M. Brucklacher, Matthew Ford, William E. Sonntag, Willard M. Freeman

    Research output: Contribution to journalArticle

    28 Citations (Scopus)

    Abstract

    Background: The necessity of including both males and females in molecular neuroscience research is now well understood. However, there is relatively limited basic biological data on brain sex differences across the lifespan despite the differences in age-related neurological dysfunction and disease between males and females. Methods: Whole genome gene expression of young (3 months), adult (12 months), and old (24 months) male and female C57BL6 mice hippocampus was analyzed. Subsequent bioinformatic analyses and confirmations of age-related changes and sex differences in hippocampal gene and protein expression were performed. Results: Males and females demonstrate both common expression changes with aging and marked sex differences in the nature and magnitude of the aging responses. Age-related hippocampal induction of neuroinflammatory gene expression was sexually divergent and enriched for microglia-specific genes such as complement pathway components. Sexually divergent C1q protein expression was confirmed by immunoblotting and immunohistochemistry. Similar patterns of cortical sexually divergent gene expression were also evident. Additionally, inter-animal gene expression variability increased with aging in males, but not females. Conclusions: These findings demonstrate sexually divergent neuroinflammation with aging that may contribute to sex differences in age-related neurological diseases such as stroke and Alzheimer's, specifically in the complement system. The increased expression variability in males suggests a loss of fidelity in gene expression regulation with aging. These findings reveal a central role of sex in the transcriptomic response of the hippocampus to aging that warrants further, in depth, investigations.

    Original languageEnglish (US)
    Article number141
    JournalJournal of Neuroinflammation
    Volume14
    Issue number1
    DOIs
    StatePublished - Jul 21 2017

    Fingerprint

    Sex Characteristics
    Gene Expression
    Hippocampus
    Gene Expression Regulation
    Microglia
    Neurosciences
    Computational Biology
    Immunoblotting
    Proteins
    Immunohistochemistry
    Stroke
    Genome
    Brain
    Research
    Genes

    Keywords

    • Aging
    • Brain
    • Gene expression
    • Neuroinflammation
    • Sex differences

    ASJC Scopus subject areas

    • Neuroscience(all)
    • Immunology
    • Neurology
    • Cellular and Molecular Neuroscience

    Cite this

    Mangold, C. A., Wronowski, B., Du, M., Masser, D. R., Hadad, N., Bixler, G. V., ... Freeman, W. M. (2017). Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging. Journal of Neuroinflammation, 14(1), [141]. https://doi.org/10.1186/s12974-017-0920-8

    Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging. / Mangold, Colleen A.; Wronowski, Benjamin; Du, Mei; Masser, Dustin R.; Hadad, Niran; Bixler, Georgina V.; Brucklacher, Robert M.; Ford, Matthew; Sonntag, William E.; Freeman, Willard M.

    In: Journal of Neuroinflammation, Vol. 14, No. 1, 141, 21.07.2017.

    Research output: Contribution to journalArticle

    Mangold, CA, Wronowski, B, Du, M, Masser, DR, Hadad, N, Bixler, GV, Brucklacher, RM, Ford, M, Sonntag, WE & Freeman, WM 2017, 'Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging', Journal of Neuroinflammation, vol. 14, no. 1, 141. https://doi.org/10.1186/s12974-017-0920-8
    Mangold, Colleen A. ; Wronowski, Benjamin ; Du, Mei ; Masser, Dustin R. ; Hadad, Niran ; Bixler, Georgina V. ; Brucklacher, Robert M. ; Ford, Matthew ; Sonntag, William E. ; Freeman, Willard M. / Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging. In: Journal of Neuroinflammation. 2017 ; Vol. 14, No. 1.
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    abstract = "Background: The necessity of including both males and females in molecular neuroscience research is now well understood. However, there is relatively limited basic biological data on brain sex differences across the lifespan despite the differences in age-related neurological dysfunction and disease between males and females. Methods: Whole genome gene expression of young (3 months), adult (12 months), and old (24 months) male and female C57BL6 mice hippocampus was analyzed. Subsequent bioinformatic analyses and confirmations of age-related changes and sex differences in hippocampal gene and protein expression were performed. Results: Males and females demonstrate both common expression changes with aging and marked sex differences in the nature and magnitude of the aging responses. Age-related hippocampal induction of neuroinflammatory gene expression was sexually divergent and enriched for microglia-specific genes such as complement pathway components. Sexually divergent C1q protein expression was confirmed by immunoblotting and immunohistochemistry. Similar patterns of cortical sexually divergent gene expression were also evident. Additionally, inter-animal gene expression variability increased with aging in males, but not females. Conclusions: These findings demonstrate sexually divergent neuroinflammation with aging that may contribute to sex differences in age-related neurological diseases such as stroke and Alzheimer's, specifically in the complement system. The increased expression variability in males suggests a loss of fidelity in gene expression regulation with aging. These findings reveal a central role of sex in the transcriptomic response of the hippocampus to aging that warrants further, in depth, investigations.",
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    AU - Bixler, Georgina V.

    AU - Brucklacher, Robert M.

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