Alzheimer’s: Why are women more likely to get sick?

Jack john January 25, 2023

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The answer could be given to us by a mutated immune protein that damages brain connections, much more common in the brains of women than men.

In the study, published in Science Advances, researchers from Scripps Research and the Massachusetts Institute of Technology (MIT) found that a particularly harmful form of an inflammatory immune protein called complement C3 was present at much higher levels in the brains of deceased women. with the disease, compared to deceased men. Researchers have also demonstrated that estrogen , whose production decreases during menopause, normally protects against the creation of this form of C3 complement.

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

For Alzheimer’s, the most common form of dementia that occurs with aging, there is no approved treatment that can halt the disease process, let alone reverse it. The shortcomings of the treatments reflect the fact that scientists have never fully understood how it develops. Scientists don’t even 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 a modified type of C3 complement, a process called S-nitrosylation of the protein. 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 block of proteins, forming a “SNO protein.”modified. Modifications of proteins by small groups of atoms such as nitric oxide are common in cells and typically turn the functions of a target protein on or off. 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 may be a key driver of Alzheimer’s and other neurodegenerative disorders.

For the new study, the researchers used novel S-nitrosylation detection methods so they could quantify the changed proteins in 40 postmortem human brains. The brains came from people who died of Alzheimer’s, and each group was evenly split 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 were some that have already been linked to Alzheimer’s disease, including complement C3. Surprisingly, the levels of S-nitrosylated C3 (SNO-C3) were more than six times higher in female brains than to the male ones.

Why is SNO-C3 more common in female Alzheimer’s brains?

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’. For more than 30 years, scientists have known that brains with Alzheimer’s have higher levels of complement proteins and other markers of inflammation than neurologically normal brains. More recent research has shown in particular that complement proteins can trigger the brain’s resident immune cells, called microglia, to destroy synapses, the connection points through which neurons send signals to one another.

It has long been shown that the female hormone estrogen may have protective effects on the brain under certain conditions; the researchers therefore hypothesized that estrogen specifically protects women’s brains from S-nitrosylation of C3 and that this protection is lost when estrogen levels drop sharply with menopause . Experiments conducted on cultured human brain cells corroborated this hypothesis, revealing that SNO-C3 increases when estrogen (β-estradiol) levels decrease, due to the activation of an enzyme that produces nitric oxide (NO) in the cells. brain cells. This increase in SNO-C3 activates the destruction of synapses by microglia.

“Why women are more likely to get Alzheimer’s 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 get older,” Lipton says.

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