Human pregnancy zone protein stabilizes misfoldedproteins including preeclampsia- and Alzheimer’s-associated amyloid beta peptide

Protein misfolding underlies the pathology of a large number of

human disorders, many of which are age-related. An exception to

this is preeclampsia, a leading cause of pregnancy-associated

morbidity and mortality in which misfolded proteins accumulate

in body fluids and the placenta. We demonstrate that pregnancy

zone protein (PZP), which is dramatically elevated in maternal

plasma during pregnancy, efficiently inhibits in vitro the aggregation

of misfolded proteins, including the amyloid beta peptide (Aβ)

that is implicated in preeclampsia as well as with Alzheimer’s disease.

The mechanism by which this inhibition occurs involves the

formation of stable complexes between PZP and monomeric Aβ or

small soluble Aβ oligomers formed early in the aggregation pathway.

The chaperone activity of PZP is more efficient than that of

the closely related protein alpha-2-macroglobulin (α2M), although

the chaperone activity of α2M is enhanced by inducing its dissociation

into PZP-like dimers. By immunohistochemistry analysis, PZP

is found primarily in extravillous trophoblasts in the placenta. In

severe preeclampsia, PZP-positive extravillous trophoblasts are adjacent

to extracellular plaques containing Aβ, but PZP is not abundant

within extracellular plaques. Our data support the conclusion

that the up-regulation of PZP during pregnancy represents a major

maternal adaptation that helps to maintain extracellular proteostasis

during gestation in humans. We propose that overwhelming or disrupting

the chaperone function of PZP could underlie the accumulation

of misfolded proteins in vivo. Attempts to characterize extracellular

proteostasis in pregnancy will potentially have broad-reaching significance

for understanding disease-related protein misfolding.