The Role of Apolipoprotein E in Pregnancy-Associated Protein Misfolding and Risk of Preeclampsia

Preeclampsia is a life-threatening pregnancy disorder responsible for >70,000 maternal and 500,000 fetal deaths annually. Currently, there is no cure for preeclampsia, apart from the emergent delivery of the fetus and the placenta. Although several pathophysiologic processes are implicated, our understanding of preeclampsia causation remains limited due to highly indistinct and heterogeneous processes. Evidence from our lab and others has identified preeclampsia as a protein misfolding disorder marked by an accumulation of abnormal conformations of misfolded proteins (including β-amyloid) in urine, serum, and placenta. Protein misfolding and aggregation have been studied extensively in prototype protein conformational disorders such as Alzheimer’s (AD) and targeting of these pathogenic processes has recently led to new treatment modalities. Herein, using human cohorts and mouse models, we investigated the link between pregnancyassociated protein misfolding manifesting as preeclampsia and Apolipoprotein E (APOE), a polymorphic gene with well-established roles in β-amyloid deposition in the brain. In humans, APOE has three naturally occurring alleles: APOE3 the non-pathogenic allele; APOE2, which is protective against AD; and APOE4, which increases the risk of AD up to 15-fold. In a well-characterized cohort of mother-newborn dyads, we demonstrate that fetal APOE4 genotype and female sex increase the risk of preeclampsia manifesting with fetal growth restriction (FGR). Importantly, fetal APOE genotype strongly influenced APOE mRNA and protein expression in the human placenta. Our research revealed, for the first time in humans, that placental macrophages (Hofbauer cells), which share common ontogenetic origins with brain microglia and are known to decrease in number in PE, synthesize APOE. This observation was further validated in a combined mouse model of PE and AD induced by reduced uteroplacental perfusion (RUPP) in EFAD mice which express five human AD transgenes and human APOE. Induction of PE-like symptomatology by RUPP significantly decreased the number of placental macrophages but upregulated APOE transcription in the mouse placenta. RUPP also decreased placental efficiency in both APOE3 and APOE4 mice but only APOE4 mice developed FGR, mimicking the human phenotype. These findings suggest that APOE and placental macrophages may play a role in maintaining homeostasis and optimal fetal growth during placental adaptation to stress.

Author dc:creator

• Mondoukpe Seyive Bani A Medegan Fagla (24399704)

• Health Sciences, Obstetrics and Gynecology
• Biology, Physiology

Statement dc:rights

• In Copyright

DOI dc:identifier

https://doi.org/10.25417/uic.32994185.v1

OAI identifier oai:identifier

oai:figshare.com:article/32994185