Alzheimer's-linked protein is major cause of preeclampsia - study

Researchers from Western University in London and Brown University in Rhode Island have taken significant steps toward identifying the cause of preeclampsia and finding potential treatment.

Preeclampsia is a pregnancy complication that affects up to eight percent of pregnancies globally and is the leading cause of maternal and fetal mortality due to premature delivery, complications with the placenta, and lack of oxygen.

The research, led by Drs. Kun Ping Lu and Xiao Zhen Zhou at Western, and Drs. Surendra Sharma and Sukanta Jash at Brown, have identified a toxic protein, called cis P-tau, in the blood and placenta of preeclampsia patients.

According to the study published in Nature Communications, cis P-tau is a central cause of preeclampsia and plays a major role in causing the deadly complication.

“The root cause of preeclampsia has (so far) remained unknown, and without a known cause there has been no cure. Preterm delivery is the only life-saving measure,” said Lu, professor of biochemistry and oncology at  Schulich School of Medicine & Dentistry. Lu is also a Western Research Chair in Biotherapeutics.

“Our study identifies cis P-tau as a crucial culprit and biomarker for preeclampsia. It can be used for early diagnosis of the complication and is a crucial therapeutic target,” said Sharma, who recently retired from his Brown roles as a professor of pathology and laboratory medicine (research) and professor of pediatrics (research).

Sharma, a leading preeclampsia researcher, and his team identified that preeclampsia and diseases like Alzheimer’s had similar root causes related to protein issues in 2016 and their new research builds on that initial finding.

Until now, cis P-tau was mainly associated with neurological disorders like Alzheimer’s disease, traumatic brain injuries (TBI), and stroke. This association was discovered by Lu and Zhou in 2015 as a result of their decades of research on the role of tau protein in cancer and Alzheimer’s.

An antibody developed by Zhou in 2012 to target only the toxic protein while leaving its healthy counterpart unscathed is currently undergoing clinical trials in human patients suffering from TBI and Alzheimer’s Disease. The antibody has shown promising results in animal models and human cell cultures in treating the brain conditions.

The researchers became curious whether the same antibody could work as a potential treatment for preeclampsia and after testing the antibody in mouse models they found interesting results.

“In this study, we found the cis P-tau antibody efficiently depleted the toxic protein in the blood and placenta, and corrected all features associated with preeclampsia in mice. Clinical features of preeclampsia, like elevated blood pressure, excessive protein in urine, and fetal growth restriction, among others, were eliminated and pregnancy was normal,” said Sharma.

Black and Hispanic women are more susceptible

Preeclampsia disproportionately impacts Black and Hispanic women, a fact that was brought to light following the death of American track and field champion Tori Bowie earlier this year. 

A gold, silver, and bronze medalist in the 2016 Olympic Games, Bowie, 32, was found dead in her bed on May 2, 2023, while approximately eight months pregnant. According to the autopsy report the complications may have involved eclampsia, a severe form of preeclampsia that can cause high blood pressure, headaches, blurry vision, and convulsions.

“Research has shown that women of certain races have genes that could possibly lead to higher than average blood pressure levels, eventually creating conditions for preeclampsia during pregnancy. However, it’s also true that in many low socio-economic countries, there’s no registry to record PE cases. So, its link to other environmental factors is still unclear,” said Sharma.

Preeclampsia and the brain

Recent research has also shed light on preeclampsia’s long-term impacts and possible links to brain health.

“Preeclampsia presents immediate dangers to both the mother and fetus, but its long-term effects are less understood and still unfolding,” said Sharma. 

“Research has suggested a heightened risk of dementia later in life for both mothers who have experienced preeclampsia and their children.” However, the causal link between preeclampsia and dementia is not known.

The researchers stated that this new study may have found the underlying cause of the complex relationship between preeclampsia and brain health.

“Our study adds another layer to this complexity. For the first time, we’ve identified significant levels of cis P-tau outside the brain in the placenta and blood of preeclampsia patients. This suggests a deeper connection between preeclampsia and brain-related issues,” said Jash, the lead author of the study, and assistant professor of molecular biology, cell biology, and biochemistry (research), and pediatrics (research) at Brown.

How the body responds to stress may also be a potential factor in the onset of preeclampsia.

“Although genetics play a role, factors like stress could be an important piece of the puzzle. Understanding how stress and other environmental factors intersect with biological markers like cis P-tau may offer a more complete picture,” said Jash. 

A stress-response enzyme

Lu and Zhou discovered the stress-response enzyme called Pin1 in 1996 and 1997. It is a protein in the cells that activates in response to stressors, such as environmental challenges, toxins, or physiological changes.

“Pin1 plays a pivotal role in keeping proteins, including the tau protein, in the functional shape during stress. When Pin1 becomes inactivated, it leads to the formation of a toxic, misshapen, variant of tau –  cis P-tau,” said Zhou, associate professor, of pathology and laboratory medicine at Schulich Medicine & Dentistry.

The Pin1 enzyme is a major part of cancer signaling networks, turning on numerous cancer-causing proteins and turning off many cancer-suppressing ones. It is found in high levels in most human cancers and is particularly active in cancer stem cells.

“Essentially, when Pin1 is activated, it can lead to cancer. On the other hand, when there’s a decrease or deactivation in Pin1, it results in the formation of the toxic protein cis P-tau, which leads to memory loss in Alzheimer’s and after TBI or stroke. Now, we’ve uncovered its connection to preeclampsia as well,” said Zhou.

“The results have far-reaching implications. This could revolutionize how we understand and treat a range of conditions, from pregnancy-related issues to brain disorders,” said Lu.