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bioRxiv · 10.1101/2023.07.12.548731

Exploring the parity paradox: Differential effects on neuroplasticity and neuroinflammation by APOEe4 genotype at middle-age

Lee, B.·Cevizci, M.·Lieblich, S.·Ibrahim, M.·Wen, Y.·Eid, R.·Lamers, Y.·Guterman, P. D.·Galea, L.
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Abstract

Female sex and Apolipoprotein E (APOE) {varepsilon}4 genotype are top non-modifiable risk factors for Alzheimers 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 APOE{varepsilon}4 genotype by examining behavioural and neural biomarkers of brain health in middle-aged female rats. Our findings show that primiparous (parous one time) hAPOE{varepsilon}4 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 hAPOE{varepsilon}4 genotype synergistically modulate neuroinflammatory markers in the ventral hippocampus. Collectively, these findings demonstrate that previous parity in hAPOE{varepsilon}4 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. O_LSTHighlightsC_LSTO_LIhAPOE{varepsilon}4 rats made more errors and used a non-spatial cognitive strategy C_LIO_LIPrimiparous hAPOE{varepsilon}4 rats increased use of a non-spatial cognitive strategy C_LIO_LIParity increased neurogenesis in wildtype rats, but decreased it in hAPOE{varepsilon}4 rats C_LIO_LIPrimiparous hAPOE{varepsilon}4 rats had less active new neurons in response to memory retrieval C_LIO_LIParity and hAPOE{varepsilon}4 affect the neuroimmune milieu in a region-specific manner C_LI

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Lee, B., Cevizci, M., Lieblich, S., Ibrahim, M., Wen, Y., Eid, R., Lamers, Y., Guterman, P. D., Galea, L.. 2023-07-13. Exploring the parity paradox: Differential effects on neuroplasticity and neuroinflammation by APOEe4 genotype at middle-age. https://doi.org/10.1101/2023.07.12.548731

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