Scientists at The Scripps Research Institute and the Massachusetts Institute of Technology (MIT) have uncovered clues to the molecular cause of Alzheimer’s disease — clues that could also explain why women are at higher risk for the disease.
In a study reported on December 14, 2022, scientific progressThe researchers found that a particularly harmful chemically modified form of an inflammatory immune protein called complement C3 was present in much higher levels in the brains of women who died of the disease compared with men who died of the disease. They also showed that estrogen — whose production declines during menopause — normally prevents the production of this form of complement C3.
“Our new findings suggest that chemical modifications to components of the complement system help drive Alzheimer’s disease and may explain, at least in part, why the disease predominantly affects women,” said study senior author Stuart Lipton, MD, PhD, professor and Step said. Family Foundation Chair, Department of Molecular Medicine, The Scripps Research Institute and clinical neurologist in La Jolla, CA.
The research was done in collaboration with a team led by Steven Tannenbaum, Ph.D., professor of bioengineering, chemistry and toxicology at MIT.
Alzheimer’s disease is the most common form of dementia that occurs with age, currently afflicting approximately 6 million people in the United States alone. It’s invariably fatal, usually occurs within a decade of onset, and there are no approved treatments that can stop the disease process, let alone reverse it. The treatment’s shortcomings reflect the fact that scientists never fully understand how Alzheimer’s develops. Scientists also don’t fully understand why women account for nearly two-thirds of cases.
Lipton’s lab studies biochemical and molecular events that may lead to neurodegenerative disease, including the chemical reaction that forms a modified form of complement C3 — a process called protein S-nitrosylation. Lipton and his colleagues previously discovered this chemical reaction, which occurs when nitric oxide (NO)-related molecules bind tightly to sulfur atoms (S) on specific amino acid building blocks of proteins to form modified “SNO proteins.” kind of reaction. “Protein modifications by small clusters of atoms such as NO are common in cells, often activating or deactivating the function of a target protein. S-nitrosylation is harder to study than other protein modifications for technical reasons, but Lipton suspects that these The “SNO storm” may be a key factor in Alzheimer’s and other neurodegenerative diseases.
For the new study, the researchers used a new method of detecting S-nitrosylation to quantify the modified proteins in 40 postmortem human brains. Half the brains came from people who died of Alzheimer’s and half from people who didn’t—each group was divided equally between men and women.
In these brains, the scientists found 1,449 different S-nitrosylated proteins. Among the proteins most commonly modified in this way, several have been implicated in Alzheimer’s disease, including complement C3. Strikingly, 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 ancient part of the human immune system. It consists of a family of proteins, including C3, that can activate each other in what is known as the “complement cascade” to drive inflammation. For more than 30 years, scientists have known that the brains of people with Alzheimer’s disease have higher levels of complement proteins and other markers of inflammation compared with neurologically normal brains. In particular, recent research has shown that complement proteins can trigger brain-resident immune cells called microglia to destroy synapses — the junctions through which neurons send signals to each other. Many researchers now suspect that this mechanism of damaging synapses underlies at least in part the Alzheimer’s disease process, and the loss of synapses has been shown to be significantly associated with cognitive decline in the Alzheimer’s brain.
Why is SNO-C3 more common in the brains of women with Alzheimer’s? There has long been evidence that the female hormone estrogen is brain-protective under certain conditions; therefore, researchers hypothesized that estrogen specifically protects the female brain from C3 S-nitrosylation—as estrogen levels increase with This protection disappears when the sharp decline occurs during menopause. Experiments on cultured human brain cells support this hypothesis, showing that SNO-C3 increases as estrogen (beta-estradiol) levels fall, due to the activation of an enzyme that produces NO in brain cells Sincerely. This increase in SNO-C3 activates microglial destruction of synapses.
“Why women are more susceptible to Alzheimer’s has long been a mystery, but I think our results represent an important piece of the puzzle that mechanistically explains women’s greater vulnerability as they age, ’ said Lipton.
He and his colleagues now hope to conduct further experiments with denitrosating compounds — removing the SNO modification — to see if they can reduce pathology in animal models of Alzheimer’s and eventually in humans.