Preeclampsia is a pregnancy-specific disorder of unknown etiology and a leading contributor to maternal and perinatal morbidity and mortality worldwide. Because there is no cure other than delivery,
preeclampsia is the leading cause of iatrogenic
preterm birth. We show that
preeclampsia shares pathophysiologic features with recognized
protein misfolding disorders. These features include urine congophilia (affinity for the amyloidophilic
dye Congo red), affinity for conformational state-dependent
antibodies, and dysregulation of prototype
proteolytic enzymes involved in
amyloid precursor
protein (APP) processing. Assessment of global
protein misfolding load in pregnancy based on urine congophilia (
Congo red dot test) carries diagnostic and prognostic potential for
preeclampsia. We used conformational state-dependent
antibodies to demonstrate the presence of generic supramolecular assemblies (prefibrillar oligomers and annular protofibrils), which vary in quantitative and qualitative representation with
preeclampsia severity. In the first attempt to characterize the
preeclampsia misfoldome, we report that the urine congophilic material includes proteoforms of
ceruloplasmin,
immunoglobulin free light chains, SERPINA1,
albumin, interferon-inducible
protein 6-16, and Alzheimer's β-
amyloid. The human placenta abundantly expresses APP along with prototype APP-processing
enzymes, of which the α-
secretase ADAM10, the β-
secretases BACE1 and BACE2, and the γ-
secretase presenilin-1 were all up-regulated in
preeclampsia. The presence of β-
amyloid aggregates in placentas of women with
preeclampsia and
fetal growth restriction further supports the notion that this condition should join the growing list of
protein conformational disorders. If these aggregates play a pathophysiologic role, our findings may lead to treatment for
preeclampsia.