Alzheimer’s Proteins Linked to Placental Defects in Preeclampsia
Amyloid-β clumps triggered by low oxygen may block placental formation in preeclampsia.
A protein typically associated with Alzheimer’s disease may be the hidden culprit behind a severe pregnancy complication.
A team at Wakayama Medical University has identified that oxygen-starved placental cells produce toxic protein clumps that prevent the placenta from forming correctly. Similar clumps are also implicated in Alzheimer’s disease.
The link between amyloid-β and preeclampsia
Preeclampsia affects between 3–8% of pregnancies worldwide, leading to high blood pressure and organ damage that poses a significant risk to the health of the mother and the developing fetus. While blood pressure changes can be managed to some degree with medication, the only complete cure is to deliver the baby and the placenta.
Low oxygen levels, known as hypoxia, and poor placenta formation have been linked to preeclampsia; however, the exact cause of the condition is unknown.
Earlier studies found clumps of amyloid-β (Aβ) in these placentas, the same protein associated with Alzheimer's disease.
“Although Aβ is present in human placentas and accumulates in preeclamptic placentas, the production and role of Aβ in the human placenta remain unclear,” said the authors of the latest study.
Hypoxia in the brain can increase Aβ production, increasing the risk of developing Alzheimer's disease. But until now, scientists did not know how these proteins affected pregnancy.
“We therefore hypothesized that hypoxia might increase Aβ production in preeclamptic placentas, leading to the formation of toxic Aβ aggregates that inhibit placental function,” explained corresponding author Dr. Kazuchika Nishitsuji, an associate professor from Wakayama Medical University.
The new study investigated whether these protein clumps interfere with a process called syncytialization, which allows placental cells to fuse and create a protective layer for the fetus. This layer manages the exchange of nutrients and gases between the mother and baby. If this process fails, the placenta cannot function correctly.
Hypoxia triggers protein clumps in preeclampsia
The team compared placental samples from five women with preeclampsia and five women with healthy pregnancies. They used lab-grown placental cells and exposed them to low oxygen levels of 2% O2. The researchers then used immunohistochemistry and Western blotting to track protein levels in the cells.
Genetic analysis showed that the low-oxygen response protein, HIF-1α, directly signaled the cell to produce more BACE1 enzyme, resulting in higher Aβ production.
BACE1
An enzyme that functions as a “molecular scissor” to produce Aβ proteins.
However, Aβ did not just appear; it formed long, thread-like structures called fibrils. These fibrils negatively impacted cell development; When Aβ42 fibrils were present, the cells secreted less hCG and syncytin-1—markers of healthy placental fusion.
hCG (Human chorionic gonadotropin)
A hormone produced by the placenta that supports pregnancy and serves as a measure of placental health.
Syncytin-1
A specialized protein that allows placental cells to fuse into a single protective layer.
Aβ monomers, single protein units, did not cause the same damage; only the aggregated fibrils blocked the cells from merging into the protective syncytiotrophoblast layer.
The Aβ fibrils damaged the proteins holding cells together by triggering excessive autophagy, specifically ZO-1 and E-cadherin. By over-activating this process, the Aβ clumps prevented the placenta from forming the barrier necessary to support the fetus.
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Autophagy
A natural cellular process for clearing out damaged components; however, if over-activated, it can destroy healthy cell structures.
ZO-1
A protein that creates tight seals between neighboring cells to maintain the strength and stability of the placental barrier.
E-cadherin
A protein that functions as a primary glue for cells, which is necessary for them to fuse into a single, protective layer.
Treating preeclampsia as a placental proteinopathy
The findings suggest that preeclampsia should be viewed as a “proteinopathy.” This term describes diseases like Alzheimer’s or Parkinson’s, where misfolded proteins cause damage. If Aβ is a driver of the condition, BACE1 inhibitors or other protein-targeting drugs could be used to treat preeclampsia during pregnancy.
However, while the lab results are clear, the human data needs more support. The clinical sample size was small, with only five patients per group, and lab-grown cells do not perfectly mirror a living body.
“Additional studies using animal models will be necessary to elucidate the significance of Aβ production and deposition in the physiology and pathology of the placenta,” said Nishitsuji.
Future research might also focus on using Aβ as a warning sign. If these proteins can be detected early in a pregnancy, they could be used to predict who will develop preeclampsia.
“Understanding the mechanisms underlying placental defects is important for the prevention of preeclampsia and development of novel preeclampsia therapies,” Nishitsuji added.
Reference: Nishioka K, Ikezaki M, Iwahashi N, et al. Amyloid-β fibrils accumulated in preeclamptic placentas suppress cytotrophoblast syncytialization. Life Sci Alliance. 2026;9(4):e202503453. doi: 10.26508/lsa.202503453
This article is a rework of a press release issued by Rockefeller University Press. Material has been edited for length and content.
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