Pregnancy History and Loss of Normal PSEN2 Function Impact Female Late-Life Cognitive Processing, Inhibitory Signaling, and Gliosis

Background. Alzheimer's disease (AD) is well-documented to be more progressive in affected females. It is thus critical to define how female-specific life experiences interact with AD-related risk factors to impact disease trajectory and functional burden. For example, pregnancy exerts dramatic influences on the maternal immune system, behavior, and neuroplasticity, specifically in hippocampal and limbic structures. The long-term clinical impacts from pregnancy history (parity) on late-life AD outcomes are, however, conflicting. Thus, we investigated the late-life functional impacts of parity on rodent cognitive function, inhibitory neuron density, and glial biology with loss of normal function of the AD-related risk factor, presenilin 2 (PSEN2). Methods. Female PSEN2 knockout (KO) and wild-type (WT) mice with (multiparous) and without (nulliparous) pregnancy history were challenged at 10-15 months-old in the T-maze (TM) and Open Field Test (OFT), followed by immunofluorescence for neuronal signaling and gliosis markers. Results. Neither parity history nor PSEN2 deficiency impacted hippocampally-mediated spatial working memory of aged female mice in the TM. However, both PSEN2 KO and multiparous mice exhibited decreased OFT locomotor behavior. Multiparous mice also showed reduced OFT center zone exploration (p=0.0045) suggesting a more anxious phenotype. Parity history generally increased inhibitory marker expression in dorsal hippocampus (p=0.017), prefrontal cortex (p=0.021), and amygdala (p=0.035). Parity generally blunted oligodendrocyte marker expression in CA1 (p<0.05), while boosting astrocyte and microglia marker expression in CA3 of dorsal hippocampus. Conclusion. This work suggests that although parity history and PSEN2 deficiency exert individual differing age-related effects on cognition and neurobiology, they do not act synergistically.