Biology of Sex Differences Best Poster Abstracts2024 BSD Poster Award
Jennifer E Richard, CAMH & University of Gothenburg JE Richard1, 2, S Lieblich3, KA Go1, R Rechlin3, TFL Splinter1, M Cevizci3, LAM Galea11Centre for Addiction and Mental Health (CAMH), CA, 2University of Gothenburg, SE, 3University of British Columbia, CA Risk factors for Alzheimer’s disease (AD) include advancing age, APOE4 allele and female sex. Females undergo unique experiences, such as pregnancy and childbirth, which may alter AD risk. Pregnancy results in physiological changes to the metabolic system and can alter brain aging. Accumulating evidence suggests a role for metabolic dysfunction in AD, and middle age may be an especially vulnerable period for females due to estrogen loss. We investigated if parity and body weight affect learning and memory in middle-aged females. We also explored whether estradiol (E2), a treatment for menopausal symptoms, can mitigate potential negative effects of obesity on metabolic and brain health. Our results show that APOE4 rats fed a standard diet (SD) had higher body weights than wild type (WT) females at middle age, regardless of parity. Four weeks on a high-fat high-sugar diet (western diet; WD) resulted in increased body weight compared to SD, with nulliparous (N; never mothered) gaining more than primiparous (mothered once), regardless of genotype. Preliminary data suggest that increased body weight is negatively associated with contextual fear condition memory in APOE4 rats. When taking parity into account, this association was only present in N hAPOE4 rats. E2 reduced body weight in WD females with a larger loss in WT than in APOE4 rats. E2 may protect against the detrimental effects of WD on memory in APOE4 N rats. Our preliminary data suggest that WD exposure at middle age has greater impact on metabolic health in N rats of both genotypes and may be especially detrimental to memory in N APOE4 carriers, and E2 may be protective against these effects.Funded by CIHR.
Ibrahim Khodabocus, University of Alberta I. Khodabocus, J. Vu, R. Roshmi, A. Noppers, S. Liu, J. Rachid, C. Holody, H. Lemieux, S. Bourque; Faculty of Medicine & Dentistry, University of Alberta Sepsis is estimated to underlie 20% of all global deaths. Males appear to be more susceptible to sepsis-induced organ injury than females, although the mechanisms underlying these sex-differences are unclear. Here, we studied the impact of fecal slurry-induced peritonitis (FIP) on mitochondrial function in male and female mice to gain insight into the sex-specific metabolic consequences of sepsis. Methods: C57BL/6 mice were injected with fecal slurry (FS, 0.55 mg/g) or vehicle. Buprenorphine (0.5 mg/kg, at 4h), Ringer's Lactate (15 mL/kg, at 12h) and Imipenem (25 mg/kg, at 12h) were administered post FIP-induction. At 4h, 12h, and 24h post-FIP, mice were euthanized, and tissues were collected; liver and kidney homogenates were assessed for mitochondrial function by high resolution respirometry. Biochemical assays were used to assess mitochondrial content and oxidative stress (8-oxo-dG). Results: FIP caused: (1) no changes in renal mitochondrial content, but reduced content in the liver of males (P=0.012), but not females (P=0.095) by 24h; (2) reduced respiration through complex(C)II in the renal medulla of males (P=0.002), but not females (P=0.75), as early as 4h post-FIP; (3) increased respiration through CI in kidneys of both males (P=0.03) and females (P=0.006) by 12h post-FIP, but reduced respiration through CI in the liver of males (P=0.031) and females (P=0.0005) by 12h post-FIP; (4) increased liver 8-oxo-dG in females (P=0.01), but not males (P=0.35) by 12h post-FIP. Significance: This work may provide insights into the sex differences in susceptibility to sepsis-induced organ dysfunction. Funding: CIHR Project Grant (PS178007) to SB
2023 BSD Poster Award Madeline E. Wood1, Che-Yuan Wu1, Rachel F. Buckley2, Walter Swardfager1, Mario Masellis1, Liisa Galea1, Sandra E. Black1, Jennifer S. Rabin1 1University of Toronto, 2Harvard Medical School. Menopause is associated with increased risk for vascular conditions and Alzheimer’s disease (AD) in women. In the present study, we investigated whether early menopause and vascular risk synergistically drive cognitive decline in women compared to men, and whether effects differ by APOE genotype. We included 7678 postmenopausal women (mean age=64.6±8.49 years, mean menopausal age=50.1±5.02 years) and 7678 age-matched men from the Canadian Longitudinal Study on Aging. Vascular risk was quantified with a summary score. Cognition was assessed at baseline and 3-year follow-up. Menopausal age was divided into tertiles. The bottom tertile represented early menopause (≤48) and the top two tertiles represented average/late menopause (≥49). Linear models tested interactive effects of menopause group (vs. male reference) and vascular risk on 3-year cognition, adjusting for baseline cognition, age, and education. In the setting of higher vascular risk, relative to men, women with early menopause had worse cognition (β=-0.18, p=.01), while women with average/late menopause had better cognition (β=0.11, p=.04). In analyses restricted to women, vascular risk was associated with worse cognition in women with early menopause compared to average/late menopause (β=-0.28, p<.001). Since APOE alleles differentially affect cognitive decline and AD risk, we repeated analyses stratified by APOE genotype. Sex and menopausal age modified associations between vascular risk and cognition differently across genotypes, suggesting that genetic, hormonal, and vascular contributions to cognitive decline may interact to influence sex differences in AD risk. These findings have implications for sex-specific dementia prevention strategies. 2022 BSD Poster Awards Damian N Di Florio, Mayo Clinic; DeLisa Fairweather, Mayo Clinic Myocarditis is an autoimmune disease caused by viral infections that localize to the heart and affects 3.5 times more men than women. Mitochondria are abundant in cardiomyocytes and regulate processes beyond the energetic demands of the cell. Biological sex affects properties related to mitochondria; males have more mitochondrial content than females, but females have more robust anti-oxidant responses. Because mitochondria comprise a significant portion of cardiomyocytes, are essential for normal cardiac function, and have not been thoroughly explored in the context of viral myocarditis, we investigated how mitochondria may differ in male and female Balb/c WT mice during acute myocarditis. Using pathway enrichment analysis, we analyzed bulk-tissue RNA-sequencing data from the hearts of coxsackievirus B3 infected male and female mice and healthy controls. We found that hearts from infected female mice are enriched for pathways involving mitochondrial repair, homeostasis, and anti-oxidant responses compared to males with myocarditis. Upstream regulatory analysis with TRANSFAC suggested that estrogen-related receptors (ERRs) co-regulate a sex difference in mitochondrial respiratory complex assembly with PGC1alpha; both ERR1 and PGC1alpha are significantly more expressed in females compared to males with myocarditis. Mice with myocarditis have decreased mitochondrial size during acute myocarditis indicating fission, a process mediated by the protein DRP1 during mitochondrial stress. Western blots showed that males have higher activation of DRP1 and expression of Parkin, suggesting that male mitochondria are more damaged than females. These data demonstrate that sex differences exist in mitochondrial homeostasis during viral myocarditis. Funding: Funded by the National Institutes of Health [R21 AI145356, R21 AI152318, & NIH training grant TL1 TR002380] V. Alexandra Moser V. Alexandra Moser, Cedars-Sinai Medical Center; Diego J. Reyes, Cedars-Sinai Medical Center; Emily Hatanaka, Cedars-Sinai Medical Center; Rachel M. Lipman, University of Maryland; Clive N. Svendsen, Cedars-Sinai Medical Center Several studies have demonstrated the ability of young blood or plasma to restore cognitive function in aged animals, and our lab has shown that bone marrow transplants from young to aged mice has beneficial effects on cognition and neural health. However, these strategies have significant practical drawbacks that limit their potential therapeutic value. Induced pluripotent stem cells (iPSCs) could provide an autologous therapy. Thus, we sought to identify the cell type responsible for the beneficial effects observed in studies using young plasma and bone marrow. We differentiated iPSCs into macrophages (iMACs) and administered these cells to aged, genetically immunocompromised, male and female NOD-scid-gamma (NSG) mice via tail vein injection. Our results demonstrate substantial sex differences in the effects of aging on cognitive performance, with male mice demonstrating greater age-associated deficits on spatial memory tasks. However, iMAC treatment significantly improved cognition, specifically in aged male mice. We also examined several key neuronal health indices and found that iMAC treatment and sex had effects on the synaptic transporter, VGLUT1, as well as on astrocyte and microglial numbers and morphology. These results demonstrate that iMACs have significant regenerative potential, offering a promising new therapeutic strategy. Importantly, the finding that the effects of both aging and iMAC treatment differ between males and females highlights the necessity of considering sex as a variable in therapeutic development and, more broadly, in aging research. Funding: Cedars-Sinai Center for Women’s Health and Sex Differences; Cedars-Sinai Board of Governors Regenerative Medicine Institute |