Scientists at Scripps Research and Massachusetts Institute of Technology (MIT) may have uncovered a molecular cause of Alzheimer’s that could also explain why women are at greater risk for the disease.

The team found levels of the protein complement C3 are higher in the brains of women than men who have died of Alzheimer’s. Further, they revealed that estrogen, which drops in production during menopause, normally protects against formation of complement C3. The complement system is part of the immune system and consists a family of proteins that can activate one another to drive inflammation in what is called the “complement cascade.”

The study was reported this week in Science Advances.

“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,” said study senior author Stuart Lipton, MD, PhD, professor and Step Family Foundation Endowed Chair in the Department of Molecular Medicine at Scripps Research in La Jolla, California.

The study was a collaboration 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 or reverse the disease process. Scientists have also never fully understood how Alzheimer’s develops or why women account for nearly two-thirds of cases.

There has been much study of this topic. Recently a group at University of Pittsburgh School of Medicine reported that variants in the MGMT gene were associated with Alzheimer’s disease, particularly in woman without the apolipoprotein E (APOE) ɛ4 allele.

Lipton’s lab studies neurodegenerative diseases, including the chemical reaction that forms a modified type of complement C3 in a process called protein S-nitrosylation.

He and his colleagues previously described how this chemical reaction 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.” 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. 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 researchers hypothesize that estrogen specifically protects women’s brains from C3 S-nitrosylation and this effect is lost when the levels  of this hormone fall sharply with menopause.

“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 [to Alzheimer’s] as they age,” Lipton said.

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.

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