Pregnancy History Impacts Cognitive Function and Neurobiology in Aged Presenilin 2 Null Female Mice

Abstract

RationaleAlzheimer’s disease (AD) is an age-related condition that exhibits well-documented sex differences, with females experiencing greater lifetime AD burden, worsened pathology, and more severe cognitive decline. Accordingly, it is necessary to study how female-specific experiences interact with AD-related risk factors to impact disease trajectory. For example, pregnancy exerts dramatic influences on the maternal immune system, behavior, and neuroplasticity, specifically in the hippocampus and limbic system. However, clinical evidence reports conflicting findings on the role of pregnancy history (parity) on late-life AD outcomes. Thus, to investigate the biological impacts of parity on disease outcomes, we hypothesized that parity would differentially impact cognitive function and neurobiology with loss of normal function of the AD-related risk factor presenilin 2 (PSEN2) in advanced age. MethodsFemale PSEN2 knockout (KO) and wild-type (WT) mice at 10-15 months-old with (multiparous) and without (nulliparous) pregnancy history were challenged in the T-maze (TM) and Open Field Test (OFT). This was followed by immunofluorescence for markers of neuronal circuitry and neuroinflammation. ResultsNeither pregnancy history nor loss of normal PSEN2 function impacted spatial working memory in the TM of aged female mice. However, both PSEN2 KO and multiparous mice exhibited decreased OFT locomotor behavior. Multiparous mice also showed reduced exploration in the OFT center (p=0.0045) suggesting an anxious phenotype. Pregnancy history was generally associated with increased inhibitory marker expression in the dorsal hippocampus (p=0.017), prefrontal cortex (p=0.021), and amygdala (p=0.035). ConclusionThis work suggests that although pregnancy history and loss of PSEN2 function exert individual differing age-related effects on cognition and brain pathology, they do not act synergistically.