Prenatal immune origins of brain aging differ by sex.

Autor: Goldstein JM; Department of Psychiatry, Massachusetts General Hospital (MGH), Harvard Medical School, Boston, MA, USA. jill_goldstein@hms.harvard.edu.; Department of Medicine, Harvard Medical School, Boston, MA, USA. jill_goldstein@hms.harvard.edu.; Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital, Boston, MA, USA. jill_goldstein@hms.harvard.edu., Konishi K; Department of Psychiatry, Massachusetts General Hospital (MGH), Harvard Medical School, Boston, MA, USA.; Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital, Boston, MA, USA., Aroner S; Department of Psychiatry, Massachusetts General Hospital (MGH), Harvard Medical School, Boston, MA, USA.; Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital, Boston, MA, USA., Lee H; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital, Boston, MA, USA.; Division of Biostatistics, Massachusetts General Hospital, Boston, MA, USA., Remington A; Department of Psychiatry, Massachusetts General Hospital (MGH), Harvard Medical School, Boston, MA, USA.; Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital, Boston, MA, USA., Chitnis T; Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital, Boston, MA, USA.; Department of Neurology, Brigham and Women's Hospital and MGH, Harvard Medical School, Boston, MA, USA., Buka SL; Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital, Boston, MA, USA.; Department of Epidemiology and Population Health, Brown University, Providence, RI, USA., Hornig M; Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY, USA., Tobet SA; Department of Psychiatry, Massachusetts General Hospital (MGH), Harvard Medical School, Boston, MA, USA.; Innovation Center on Sex Differences in Medicine, Massachusetts General Hospital, Boston, MA, USA.; Department of Biomedical Sciences and School of Biomedical Engineering, Colorado State University, Fort Collins, CO, USA.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2024 Nov 21. Date of Electronic Publication: 2024 Nov 21.
DOI: 10.1038/s41380-024-02798-w
Abstrakt: With an increasing aging population and Alzheimer's disease tsunami, it is critical to identify early antecedents of brain aging to target for intervention and prevention. Women and men develop and age differently, thus using a sex differences lens can contribute to identification of early risk biomarkers and resilience. There is growing evidence for fetal antecedents to adult memory impairments, potentially through disruption of maternal prenatal immune pathways. Here, we hypothesized that in utero exposure to maternal pro-inflammatory cytokines will have sex-dependent effects on specific brain circuitry regulating offspring's memory and immune function that will be retained across the lifespan. Using a unique prenatal cohort, we tested this in 204 adult offspring, equally divided by sex, who were exposed/unexposed to an adverse in utero maternal immune environment and followed into early midlife (~age 50). Functional magnetic resonance imaging results showed exposure to pro-inflammatory cytokines in utero (i.e., higher maternal IL-6 and TNF-α levels) was significantly associated with sex differences in brain activity and connectivity underlying memory circuitry and performance and with a hyperimmune state, 50 years later. In contrast, the anti-inflammatory cytokine, IL-10 alone, was not significantly associated with memory circuitry in midlife. Predictive validity of prenatal exposure was underscored by significant associations with age 7 academic achievement, also associated with age 50 memory performance. Results uniquely demonstrated that adverse levels of maternal in utero pro-inflammatory cytokines during a critical period of the sexual differentiation of the brain produced long-lasting effects on immune function and memory circuitry/function from childhood to midlife that were sex-dependent, brain region-specific, and, within women, reproductive stage-dependent.
Competing Interests: Competing interests: JMG is on the scientific advisory board and has an equity interest in Cala Health (a neuromodulation company). JMG’s interests are managed by MGH and MassGeneral Brigham HealthCare in accordance with the conflict of interest policies. However, the work in the study presented here is unrelated thus there is no conflict of interest.
(© 2024. The Author(s).)
Databáze: MEDLINE
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