Abstract
Female sex and Apolipoprotein E (APOE) ε4 genotype are top non-modifiable risk factors for Alzheimer’s disease (AD). Although female-unique experiences like parity (pregnancy and motherhood) have positive effects on neuroplasticity at middle age, previous pregnancy may also contribute to AD risk. To explore these seemingly paradoxical long-term effects of parity, we investigated the impact of parity with APOEε4 genotype by examining behavioural and neural biomarkers of brain health in middle-aged female rats. Our findings show that primiparous (parous one time) hAPOEε4 rats display increased use of a non-spatial cognitive strategy and exhibit decreased number and recruitment of new-born neurons in the ventral dentate gyrus of the hippocampus in response to spatial working memory retrieval. Furthermore, primiparity and hAPOEε4 genotype synergistically modulate neuroinflammatory markers in the ventral hippocampus. Collectively, these findings demonstrate that previous parity in hAPOEε4 rats confers an added risk to present with reduced activity and engagement of the hippocampus as well as elevated pro-inflammatory signaling, and underscores the importance of considering female-specific factors and genotype in health research.
HighlightshAPOEε4 rats made more errors and used a non-spatial cognitive strategy
Primiparous hAPOEε4 rats increased use of a non-spatial cognitive strategy
Parity increased neurogenesis in wildtype rats, but decreased it in hAPOEε4 rats
Primiparous hAPOEε4 rats had less active new neurons in response to memory retrieval
Parity and hAPOEε4 affect the neuroimmune milieu in a region-specific manner
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Abbreviations: hAPOEε4–humanized APOEε4, Aβ–amyloid-beta, p-tau–phosphorylated tau, IFN-γ– interferon-gamma, IL-1β–interleukin-1-beta, IL-4–interleukin-4, IL-5–interleukin-5, IL-6–interleukin-6, IL-10–interleukin-10, IL-13–interleukin-13, TNF-α–tumour necrosis factor-alpha, CXCL1–chemokine (CXC-motif) ligand 1, Sox2–SRY-box transcription factor 2, DCX–doublecortin, zif268–zinc finger-containing transcription factor 268, IEG–immediate early gene, Iba1–ionized calcium-binding adaptor molecule 1, IR–immunoreactive, Th–T-helper, TRP–tryptophan, KYN–kynurenine, KYNA–kynurenic acid, XA– xanthurenic acid, AA–anthranilic acid, 3-HK–3-hydroxykynurenine, 3-HAA–3-hydroxyanthranilic acid, FAD–flavin adenine dinucleotide
Funding: This work was supported by CIHR (to LAMG PJT 148662), Alzheimer’s Association and Brain Canada (to PDG AARF-17-529705), NSERC (CGS-M to BHL), UBC Marshall Scholar Program (to BHL), and the Cordula Gunter Paetzold Fellowship (to BHL).
Declarations of interest: None