Dementia-Associated Protein Provides Clues About Preeclampsia
By Deborah Borfitz
November 1, 2023 | Researchers at the University of Western Ontario and Brown University were surprised to discover an “almost identical mechanism” appearing in the blood and placenta of women with preeclampsia as has been previously found in the brains of older individuals with Alzheimer’s disease (AD), traumatic brain injury (TBI), and vascular dementia, according to Western biochemistry professor Kun Ping Lu, Ph.D., M.D. The common culprit is a toxic protein known as cis P-tau, the target of a highly specific antibody now in clinical trials as a potential treatment for AD and TBI.
In the mid-1990s, Lu and his long-term collaborator Xiao Zhen Zhou, M.D., associate professor of pathology and laboratory medicine at Western, discovered a stress response enzyme called Pin1 (peptidyl-prolyl cis–trans isomerase) whose dysregulation has the opposite impact on AD and cancer, he says. Pin1 has thus far shown considerable potential in treating neurodegenerative disease as well as stroke and sepsis—but if overexpressed it can turn on numerous cancer-causing proteins and turn off many cancer-suppressing ones.
The puzzling reverse relationship is supported by the fact that people at risk for AD are less likely to get cancer or vice versa as shown by epidemiological studies, he notes. The Pin1 enzyme beneficially helps tau do its job of maintaining functional neurons in the brain but gets depleted with age. The stress encountered by nerve cells over time appears to turn up the production of abnormal cis P-tau that Lu and Zhou have tied to the development of neurofibrillary tangles, one of the hallmarks of AD.
Preeclampsia experts at Brown, led by Drs. Surendra Sharma and Sukanta Jash, have meanwhile been busy sorting out why the dangerous pregnancy complication increases the risk of dementia for both mother and baby. So, the two groups started working together in 2019 to investigate if cis P-tau might be the link and found it was indeed the troublemaking protein, says Lu. Results of that study published recently in Nature Communications (DOI: 10.1038/s41467-023-41144-6).
It has long been theorized that stress, possibly caused by low levels of oxygen (hypoxia), prompts production of an abnormal protein that makes its way to the blood with unwelcome effects including hypertension, proteinuria (protein in the urine), and even seizures, Lu says. “I think we have finally solved the mystery of what that toxin is.”
The antibody in clinical trials, which targets the misshapen cis P-tau, was developed by Zhou in 2012 and has been licensed to Boston-based Pinteon Therapeutics. In addition to being a disease driver, the toxic protein in the blood has been shown to be one of the earliest biomarkers of AD and brain injury—five to 10 years prior to the development of tau tangles after brain injury, reports Lu.
Cis P-tau can potentially aid in the diagnosis of a wide range of diseases responding to this common stress response, says Lu. That’s because it can prompt different conformational changes to otherwise normal, useful proteins in the body, presumably driven by reduced blood flow.
A “huge percentage” of preeclampsia patients have a measurable level of cis P-tau in their blood, he adds. The hope moving forward is that a diagnostic test will be available—initially for at-risk populations such as women who are over 40, Black, or Hispanic—who could then be treated with the novel antibody.
In the latest study, researchers injected 100 microliters of blood from human preeclampsia patients into humanized tau pregnant mice and then demonstrated how the antibody succeeded in correcting all the “major features” associated with preeclampsia in the animal models, says Zhou, including elevated blood pressure, proteinuria, and fetal and placental growth restriction. The cis P-tau also effectively disappeared from the placenta.
Conversely, inhibition of Pin1 both induced cis P-tau and caused the onset of the preeclampsia-like features that progressively worsened in severity.
Work on the diagnostic test is underway that will measure cis P-tau using the stereo-specific antibody in sensitive enzyme-linked immunosorbent assay on its own or in combination with PCR methods, says Lu. It will likely find its way to the clinic ahead of the antibody treatment, which will require rigorous clinical investigation.
The potential holdup here is restrictions and fears regarding the participation of pregnant women in trials, out of concern for the fetus, he continues. One possible remedy is to enroll the small proportion of women who develop the disorder after their baby’s birth.
Postpartum preeclampsia usually happens within 48 hours of having a baby but can develop up to six weeks later. While rare, it can have serious consequences that can lead to permanent organ damage, stroke, or death, says Zhou.
The clinical implications of a diagnostic test and therapeutic treatment for preeclampsia are substantial, points out Lu. Preeclampsia affects 5% to 8% of pregnancies globally and is the top reason for maternal and fetal deaths. Its cause remains unknown, and delivery is the only available life-saving measure.
The possibility of it triggering dementia later in life in mothers and their offspring is also worrying. In a 37-year nationwide cohort study, researchers in Denmark found a 6.5 times greater risk of vascular dementia after age 65 among women who had preeclampsia years earlier (BMJ, DOI: 10.1136/bmj.k4109). Preeclampsia and vascular dementia also appeared to share susceptibility pathways.
The cis P-tau connection provides an easy explanation, Lu reiterates. TBI, stroke, and preeclampsia “all produce a toxic protein that is related to neurodegeneration.”
He and Zhou have already shown in preclinical studies that their cis P-tau antibody can prevent dementia associated with chronic traumatic encephalopathy (Nature, DOI: 10.1038/nature14658; Nature Communications, DOI: 10.1038/s41467-017-01068-4), a serious consequence of repeated TBIs documented in American football players. It is “very likely” that they will be able to show the same in humanized pregnant tau mice in preventing preeclampsia-related Alzheimer’s disease, says Lu.
The pair has separately been working on a version of the Pin1 inhibitor specific to cancer that has shown promising results for eradicating aggressive cancer (e.g., pancreatic cancer) in a preclinical model (Cell, DOI: 10.1016/j.cell.2021.07.020), says Lu. Pin1 inhibitors may be useful for treating aggressive cancers given that mice without Pin1 are normal and develop age-dependent neurodegeneration after about half of their lifespan (Nature, DOI: 10.1038/nature01832).
However, he adds, it is important to be mindful about potential side effects when manipulating Pin1 activity given the contradictory effects on cancer and dementia—two major age-related diseases on “opposite sides of the same coin.”