In the study, reported on December 14, 2022, in Science Advances, the researchers found that a particularly harmful, chemically modified form of an inflammatory immune protein called complement C3 was present at much higher levels in the brains of women who had died with the disease, compared to men who had died with the disease. They also showed that estrogen — which drops in production during menopause — normally protects against the creation of this form of complement C3.

“Our new findings suggest that chemical modification of a component of the complement system helps drive Alzheimer’s, and may explain, at least in part, why the disease predominantly affects women,” says study senior author Stuart Lipton, MD, PhD, professor and Step Family Foundation Endowed Chair in the Department of Molecular Medicine at Scripps Research and a clinical neurologist in La Jolla, California.

The study was a collaboration with a team led by Steven Tannenbaum, PhD, Post Tenure Underwood-Prescott Professor of Biological Engineering, Chemistry and Toxicology at MIT.

Alzheimer’s, the most common form of dementia that occurs with aging, currently afflicts about six million people in the U.S. alone. It is always fatal, usually within a decade of onset, and there is no approved treatment that can halt the disease process, let alone reverse it. The shortcomings of treatments reflect the fact that scientists have never fully understood how Alzheimer’s develops. Scientists also don’t know fully why women account for nearly two-thirds of cases.

Lipton’s lab studies biochemical and molecular events that may underlie neurodegenerative diseases, including the chemical reaction that forms a modified type of complement C3 — a process called protein S-nitrosylation. Lipton and his colleagues previously discovered this chemical reaction, which happens when a nitric oxide (NO)-related molecule binds tightly to a sulfur atom (S) on a particular amino acid building-block of proteins to form a modified “SNO-protein.” Protein modifications by small clusters of atoms such as NO are common in cells and typically activate or deactivate a target protein’s functions. For technical reasons, S-nitrosylation has been more difficult to study than other protein modifications, but Lipton suspects that “SNO-storms” of these proteins could be a key contributor to Alzheimer’s and other neurodegenerative disorders.

For the new study, the researchers used novel methods for detecting S-nitrosylation to quantify proteins modified in 40 postmortem human brains. Half of the brains were from people who had died of Alzheimer’s, and half were from people who hadn’t — and each group was divided equally between males and females.

In these brains, the scientists found 1,449 different proteins that had been S-nitrosylated. Among the proteins most often modified in this way, there were several that have already been tied to Alzheimer’s, including complement C3. Strikingly, the levels of S-nitrosylated C3 (SNO-C3) were more than six-fold higher in female Alzheimer’s brains compared to male Alzheimer’s brains.

The complement system is an evolutionarily older part of the human immune system. It consists of a family of proteins, including C3, that can activate one another to drive inflammation in what is called the “complement cascade.” Scientists have known for more than 30 years that Alzheimer’s brains have higher levels of complement proteins and other markers of inflammation, compared to neurologically normal brains. More recent research has shown specifically that complement proteins can trigger brain-resident immune cells called microglia to destroy synapses — the connection points through which neurons send signals to one another. Many researchers now suspect that this synapse-destroying mechanism at least partly underlies the Alzheimer’s disease process, and loss of synapses has been demonstrated to be a significant correlate of cognitive decline in Alzheimer’s brains.

Why would SNO-C3 be more common in female brains with Alzheimer’s? There has long been evidence that the female hormone estrogen can have brain-protective effects under some conditions; thus, the researchers hypothesized that estrogen specifically protects women’s brains from C3 S-nitrosylation — and this protection is lost when estrogen levels fall sharply with menopause. Experiments with cultured human brain cells supported this hypothesis, revealing that SNO-C3 increases as estrogen (?-estradiol) levels fall, due to the activation of an enzyme that makes NO in brain cells. This increase in SNO-C3 activates microglial destruction of synapses.

“Why women are more likely to get Alzheimer’s has long been a mystery, but I think our results represent an important piece of the puzzle that mechanistically explains the increased vulnerability of women as they age,” Lipton says.

He and his colleagues now hope to conduct further experiments with de-nitrosylating compounds — which remove the SNO modification — to see if they can reduce pathology in animal models of Alzheimer’s and eventually in humans.

Cluster headaches are short but extremely painful headaches that can occur many days, or even weeks, in a row. The headaches can last anywhere from 15 minutes to three hours.

“Around the world, headaches have an incredibly negative impact on people’s quality of life, both economically and socially,” said study author Caroline Ran, PhD, of the Karolinska Institutet in Stockholm, Sweden. “Our results show that people with cluster headaches not only have an increased risk of other illnesses, those with at least one additional illness missed four times as many days of work due to sickness and disability than those with just cluster headaches. They also have a higher chance of a long-term absence from work.”

The study involved 3,240 people with cluster headaches from age 16-64 in Sweden who were compared to 16,200 people who were similar in age, sex and other factors. The majority were men, which is common with cluster headache.

Researchers looked at work records and disability benefits to determine how many days during a year people were absent from work due to sickness and disability.

Among those with cluster headaches, 92%, or 2,977 people, had at least one additional illness. Of those without cluster headaches, 78%, or 12,575 people, had two or more illnesses.

Of those with cluster headaches, more women had additional illnesses than men, 96% and 90% respectively.

The average number of days a person was absent due to sickness and disability was nearly twice as high among people with cluster headaches with 63 days compared to those without cluster headaches with 34 days.

People with cluster headaches and at least one additional illness had four times as many absence days compared to people with cluster headaches who did not have an additional illness.

“Increasing our understanding of the other conditions that affect people with cluster headache and how they impact their ability to work is very important,” added Ran. “This information can help us as we make decisions on treatments, prevention and prognoses.”

A limitation of the study was that information on personal data, such as smoking, alcohol consumption and BMI, which could affect the occurrence of diseases, was not available.

The study was supported by Swedish Research Council, Swedish Brain Foundation and Mellby Gård, Region Stockholm, Märta Lundkvist Foundation and Karolinska Institutet Research Funds.

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The trials were conducted under the Partnership for Research on Ebola Vaccination (PREVAC) international consortium. PREVAC’s partner organizations include the U.S. National Institutes of Health (NIH), the French National Institute of Health and Medical Research and the London School of Hygiene & Tropical Medicine. The National Institute of Allergy and Infectious Diseases (NIAID), part of NIH, sponsored the trial in Liberia and Mali. In Liberia, the study was done in collaboration with the Liberia Ministry of Health through the Partnership for Research on Ebola Virus in Liberia program. In Mali, it was conducted in collaboration with the University Clinical Research Center and the Center for Vaccine Development-Mali.

The trials began enrollment in 2017, were conducted simultaneously and shared a placebo arm. A total of 1,400 adults and 1,401 children aged 1 year to 17 years old were randomized to receive two injections of either placebo or Ebola vaccine in one of three regimens. The Ebola vaccine regimens were Ad26.ZEBOV (supplied by Johnson & Johnson) followed eight weeks later with a booster dose of MVA-BN-Filo vaccine (supplied by manufacturer Bavarian Nordic); two doses of rVSVΔG-ZEBOV-GP (manufactured by Merck Sharp & Dohme Corp) separated by eight weeks; or one dose of the Merck vaccine followed eight weeks later by a placebo injection.

Antibody responses were observed by day 14 after the first injection of either Ad26.ZEBOV or rVSVΔG-ZEBOV-GP vaccine. The researchers say this finding is notable because vaccines against Ebola virus disease are typically administered during an outbreak and so information about how rapidly a vaccine produces an antibody effect is of potential use in efforts to protect at-risk populations. However, it is not currently known what level of antibody response reliably correlates with vaccine-induced protection against Ebola virus infection or disease. As no participants contracted Ebola virus disease during the trial, the investigators were not able to assess protection from disease.

The researchers cite several strengths of the trials, including outstanding retention of volunteers throughout the course of trial, achieved with continuing community engagement and ongoing trust-building efforts.

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Materials provided by NIH/National Institute of Allergy and Infectious Diseases. Note: Content may be edited for style and length.