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bioRxiv · 10.1101/2025.03.06.641957

Amyloid-β fibrils accumulated in preeclamptic placentas suppress syncytialization of cytotrophoblasts

Nishioka, K.·Ikezaki, M.·Iwahashi, N.·Arakawa, M.·Fukushima, M.·Mori, N.·Mizoguchi, M.·Horiuchi-Tanizaki, Y.·Fujino, M.·Tomiyama, T.·Ihara, Y.·Uchimura, K.·Ino, K.·Nishitsuji, K.
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Abstract

Cerebral deposition of fibrillar amyloid-{beta} (A{beta}) is a pathological hallmark of Alzheimers disease. While A{beta} is present in human placentas and accumulates in preeclamptic placentas characterized by poor placentation, the production and role of A{beta} in the human placenta remain unclear. Because hypoxia in mid-to-late pregnancy is a risk for preeclampsia, we found that levels of hypoxia-inducible factor 1- and {beta}-secretase (BACE-1) increased concurrently with placental A{beta} deposition in late stage preeclamptic placentas. We also found that a human cytotrophoblast (CTB) model, BeWo cells, actually produced A{beta} species, and that hypoxia increased A{beta} production and BACE-1 protein levels. A{beta}42 fibrils inhibited CTB syncytialization, a critical step in maintaining pregnancy, by inducing loss of membrane localization of cell-cell adhesion molecules. Primary human CTBs confirmed these observations. Taken together, our results suggest that increased A{beta} production in CTBs by hypoxia may lead to the formation of A{beta} fibrils, which inhibit syncytiotrophoblast formation and are detrimental to pregnancy. Thus, our results reveal the novel role of A{beta} fibrils in the pathogenesis of preeclampsia.

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Nishioka, K., Ikezaki, M., Iwahashi, N., Arakawa, M., Fukushima, M., Mori, N., Mizoguchi, M., Horiuchi-Tanizaki, Y., Fujino, M., Tomiyama, T., Ihara, Y., Uchimura, K., Ino, K., Nishitsuji, K.. 2025-03-11. Amyloid-β fibrils accumulated in preeclamptic placentas suppress syncytialization of cytotrophoblasts. https://doi.org/10.1101/2025.03.06.641957

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