Abstract WP373: Aquaporin-4 Expression is Decreased in Human Dementia Subjects and Mouse Models of Eclampsia

Hypertensive pregnancy disorders are associated with a higher risk for the development of dementia. A cohort study showed that women with a history of preeclampsia (PE) had over three times the risk of vascular dementia than women with normotensive pregnancy history. A hallmark of Alzheimer’s disease (AD) is the deposition of amyloid-beta plaques that are cleared by the glymphatic system, which maintains fluid equilibrium and eliminates metabolic waste from the CNS. Aquaporin-4 (AQP4) water channels, a key part of this system, are enriched in astrocyte endfeet surrounding microvessels and mediate the convective flow of interstitial fluid through the glymphatic pathway. This is suppressed in AD subjects before clinical symptoms appear. We hypothesized that dementia subjects would have reduced AQP4 gene expression in different brain regions compared to controls and that mice exposed to PE and eclampsia conditions would have reduced AQP4 polarization at astrocyte endfeet. We retrieved human data from the Aging, Dementia, and TBI cohort study. RNA-seq data for AQP4 were downloaded, excluding subjects with TBI, ran through a Python package, and analyzed. To model PE, we performed reduced uterine perfusion pressure (RUPP) or sham surgery on SMA-GFP mice at gestational day (GD) 13.5. To simulate eclampsia, we administered pentylenetetrazol (PTZ, a GABA antagonist, 40mg/kg) on GD 18.5, leading to 4 groups (SHAM-PTZ, SHAM+PTZ, RUPP-PTZ, RUPP+PTZ, n=3-4). After 30 minutes of monitoring, brains were collected and prepared for immunofluorescence. Sections were stained for AQP-4 and imaged using confocal microscopy. AQP4 intensity was quantified in the cortex and hippocampus. In dementia subjects, AQP4 expression was downregulated in the temporal cortex (7.3±0.4 vs 7.6±0.4 Log2Intensity; p=0.033) and parietal cortex (7.5±0.4 vs 7.7±0.3, p=0.048). There was a main effect of seizures on AQP4 expression, with decreased AQP4 expression in PTZ-treated groups in the cortex (F(1,10)=10.25, p=0.009) and hippocampus (F(1,10)=11.33, p=0.007). There was no effect of RUPP surgery or interaction between the two factors on AQP4 expression. These results suggest that the reduced AQP4 observed in the eclampsia mouse models may be a predisposing factor to the suppression of AQP4 observed in the human dementia subjects. This could explain the link between eclampsia and future dementia. Future studies will investigate AQP4 expression at postpartum timepoints in PE and eclampsia models.