Scientists from Scripps Research and the Massachusetts Institute of Technology (MIT) have found a clue to the molecular cause of Alzheimer’s disease – a clue that could also explain why women are at higher risk for the disease.
In the study, published on December 14, 2022, in Scientists progress, researchers found that a particularly harmful chemically altered form of an inflammatory immune protein called complement C3 was present at much higher levels in the brains of women who died from the disease, compared to men who died from the disease. disease. They also showed that estrogen – the production of which decreases during menopause – normally protects against the creation of this form of C3 complement.
“Our new findings suggest that chemical modification of a component of the complement system helps drive Alzheimer’s disease and may explain, at least in part, why the disease primarily affects women,” says the lead author. study, 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 disease, the most common form of dementia that occurs with aging, currently affects approximately six million people in the United States alone. It is always fatal, usually within a decade of its onset, and there are no approved treatments that can halt the disease process, let alone reverse it. The lack of treatment reflects the fact that scientists have never fully understood how Alzheimer’s disease develops. Scientists also don’t know why women account for nearly two-thirds of cases.
Lipton’s lab studies the biochemical and molecular events that may underlie neurodegenerative diseases, including the chemical reaction that forms an altered type of C3 complement – a process called protein S-nitrosylation. Lipton and his colleagues previously discovered this chemical reaction, which occurs when a molecule bound to nitric oxide (NO) binds tightly to a sulfur (S) atom on a particular amino acid building block of proteins. to form a modified “SNO protein”. “Modifications of proteins by small groups of atoms such as NO are common in cells and usually turn on or off the functions of a target protein. For technical reasons, S-nitrosylation has been more difficult to study than other protein modifications, but Lipton suspects that the “SNO storms” of these proteins could be a key contributor to Alzheimer’s disease and other diseases. other neurodegenerative disorders.
For the new study, the researchers used novel S-nitrosylation detection methods to quantify altered proteins in 40 postmortem human brains. Half of the brains came from people who died of Alzheimer’s disease, and the other half came from people who didn’t – and each group was split equally between men and women.
In these brains, the scientists found 1,449 different proteins that had been S-nitrosylated. Among the most frequently modified proteins, several have already been linked to Alzheimer’s disease, including complement C3. Strikingly, levels of S-nitrosyl C3 (SNO-C3) were more than six times higher in the brains of women with Alzheimer’s than in the brains of men with Alzheimer’s.
The complement system is an evolutionarily older part of the human immune system. It is made up of a family of proteins, including C3, that can activate each other to cause 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 specifically shown that complement proteins can trigger brain immune cells called microglia to destroy synapses – the connection points through which neurons send signals to each other. Many researchers now suspect that this mechanism of synapse destruction underlies at least part of the Alzheimer’s disease process, and loss of synapses has been shown to be a significant correlate of cognitive decline in the brain of the Alzheimer’s disease.
Why would SNO-C3 be more frequent in the brains of women with Alzheimer’s disease? There has long been evidence that estrogen, a female hormone, may have protective effects on the brain under certain conditions. thus, the researchers hypothesized that estrogen specifically protects the female brain from C3 S nitrosylation – and this protection is lost when estrogen levels drop sharply with menopause. Experiments with cultured human brain cells supported this hypothesis, revealing that SNO-C3 increases as estrogen (β-estradiol) levels decrease, due to activation of an enzyme that makes NO in the cells. brain cells. This increase in SNO-C3 activates microglial destruction of synapses.
“Why women are more susceptible to Alzheimer’s disease has long been a mystery, but I believe our findings represent an important piece of the puzzle that mechanistically explains women’s increased vulnerability as they age,” said Lipton.
He and his colleagues now hope to conduct further experiments with denitrosylation compounds – which suppress the SNO modification – to see if they can reduce pathology in animal models of Alzheimer’s disease and possibly in humans.