Date September 13, 2023
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Scientists uncover a diagnostic signal for preeclampsia that could inform treatments

The same blood biomarker that signifies Alzheimer’s disease is also a driver of the life-threatening pregnancy condition of preeclampsia, a finding that has important implications for diagnosis and treatment.

[Editor's Note: This story has been updated with Surendra Sharma's new professional role.]

PROVIDENCE, R.I. [Brown University] — A protein in cerebrospinal fluid associated with Alzheimer’s disease is also a driver of the pregnancy condition of preeclampsia, and it can influence diagnosis and treatment of the condition.

Research led by Surendra Sharma and Sukanta Jash at Brown University and Kun Ping Lu and Xia Zhen Zhou at Western University in Canada has identified the protein, cis P-tau, in the blood and placentas of people with preeclampsia. They also found that depleting cis P-tau prevented the development of preeclampsia in mice.

The researchers detailed their findings in Nature Communications.

“Our study identifies cis P-tau as a culprit and biomarker for preeclampsia,” said Sharma, who was, until recently, a Brown professor of pathology and laboratory medicine (research) and professor of pediatrics (research). “It can be used for early diagnosis of the complication and is a crucial therapeutic target.” (Sharma is now a professor of obstetrics and gynecology at the University of Texas Medical Branch in Galveston.)

Preeclampsia affects 5% to 8% 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 root cause of preeclampsia has so far remained unknown, Sharma said, and without a known cause there has been no cure.

The protein cis P-tau has mainly been associated with neurological disorders like Alzheimer’s disease, traumatic brain injuries 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.

In 2016, Sharma and his team at Brown identified that preeclampsia and diseases like Alzheimer’s had similar root causes related to protein issues.

Sharma and Jash first met Lu and Zhou in 2019 at Brown, where Lu had been invited to discuss his research. Zhou had developed an antibody to target only the toxic cis P-tau protein while leaving its healthy counterpart unscathed. (The antibody has shown promising results in animal models and human cell cultures in treating the brain conditions, and is currently being tested in clinical trials in human patients with traumatic brain injury and Alzheimer’s.)

The Brown scientists had previously discovered that cis P-tau was significantly dysregulated in the human placenta, comparable to what happens in the brains of people affected by Alzheimer’s.

The researchers became curious whether Zhou’s antibody could work as a potential treatment for preeclampsia.

In the new study, the researchers used multiple approaches to demonstrate the significance of tau in early- and late-onset preeclampsia, including measuring for cis P-tau in the blood and placenta from human patients with preeclampsia as well as depleting cis P-tau from a humanized mouse model of preeclampsia. 

“ 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. ”

Sukanta JashSukanta Jash, M.D., Ph.D. Assistant Professor of Molecular Biology, Cell Biology and Biochemistry (Research); Assistant Professor of Pediatrics (Research)

When the Brown researchers tested Zhou’s antibody in mouse models with preeclampsia, they discovered that the antibody depleted not only the cis P-tau protein but also some of the effects associated with preeclampsia.

“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,” Sharma said. “Clinical features of preeclampsia, like elevated blood pressure, excessive protein in urine and fetal growth restriction, among others, were eliminated and pregnancy was normal.”

Preeclampsia and the brain

The researchers say the findings shed light on the connections between preeclampsia and brain health.

“Preeclampsia presents immediate dangers to both the mother and fetus, but its long-term effects are less understood and still unfolding,” Sharma said. “Research has suggested a heightened risk of dementia later in life for both mothers who have experienced preeclampsia and their children.”

However, he added, the causal link between preeclampsia and dementia is not known.

“Our study adds another layer to this complexity,” said Jash, a Brown assistant professor of molecular biology, cell biology and biochemistry (research) and assistant professor of pediatrics (research). “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.”

Screening tests for the cis P-tau biomarker, combined with therapies involving the cis P-tau antibody, could change the outlook for pregnant people with preeclampsia, Jash said.

“The prospective application of cis P-tau antibody as a therapeutic intervention for preeclampsia has promise in mitigating the occurrence of subsequent neurodegenerative diseases in women who have undergone preeclampsia during pregnancy,” Jash said.

Sharma, Jash and their team at Brown have been working on developing a lab test for preeclampsia.

“These astonishing findings bring us closer to our goal of early detection of preeclampsia and therapies to treat the condition,” Sharma said.

This research was funded in part by the U.S. National Institutes of Health (P20 GM121298, 3P20GM121298-04W1, P30 GM114750); the Canada Foundation for Innovation (43257, 43822); and Canadian Institutes of Health Research (502128).