Women are more likely to develop Alzheimer’s disease, researchers find

Scientists have discovered a clue to the molecular origins of Alzheimer’s disease, which may also explain why women are more susceptible to the condition.

In a study reported on December 14, 2022, in Science Advances, researchers discovered that a particularly harmful, chemically modified inflammatory immune protein called complement C3 is found in much higher levels in the brains of women. disease, compared to men who died of disease. They also showed that estrogen – which is reduced in production during menopause – normally prevents the creation of this form of supplemental C3.

“Our new findings suggest that chemical modification of a component of the complement system helps drive Alzheimer’s, and may at least explain 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 in old age, currently affects about six million people in the US alone. It is always fatal, usually within a decade of onset, and there is no approved treatment that can stop the disease process, let alone reverse it. Treatment deficiencies reflect the fact that scientists do not fully understand how Alzheimer’s develops. Scientists also don’t fully know why women account for nearly two-thirds of cases.

Lipton’s lab studies the biochemical and molecular events that lead to neurodegenerative diseases, including the chemical reaction that creates a modified form of complement C3 – called protein S-nitrosylation. Lipton and his colleagues first discovered this chemical reaction, which occurs when a nitric oxide (NO)-related molecule attaches to a sulfur atom (S) in a specific amino acid building block of a protein to form a modified “SNO-protein.” . Protein modifications by small clusters of atoms such as NO are common in cells and usually activate or deactivate the functions of target proteins. 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 major contributor to Alzheimer’s and other neurodegenerative disorders.

For the new study, researchers used new methods to detect S-nitrosylation to quantify proteins modified in 40 postmortem human brains. Half the brains were from people who had died of Alzheimer’s, and half were 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 were S-nitrosylated. Among the proteins most often modified in this way, there were several that have been linked to Alzheimer’s, including complement C3. Surprisingly, levels of S-nitrosylated C3 (SNO-C3) were six times higher in female Alzheimer’s brains than in 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 interact with each other to activate inflammation called the “complement cascade.” Scientists have known for more than 30 years that Alzheimer’s brains have more complement proteins and other markers of inflammation than neurologically normal brains. More recent research has specifically shown that complement proteins can trigger brain-resident immune cells called microglia to destroy synapses—the connection points through which neurons send signals to each other. Many researchers now suspect that this synapse-destroying mechanism at least partially underlies the Alzheimer’s disease process, and the 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 the brains of women with Alzheimer’s? There has long been evidence that the female hormone estrogen can have a brain-protective effect in some cases; Thus, the researchers hypothesized that estrogen specifically protects the female brain from C3 S-nitrosylation–and that this protection is lost when estrogen levels drop sharply with menopause. Experiments with cultured human brain cells supported this hypothesis, showing that SNO-C3 increases as estrogen (b-estradiol) levels decrease, due to the activation of NO-forming enzymes in brain cells. This increase in SNO-C3 activates microglial destruction of synapses.

“The question of why women are more likely to develop Alzheimer’s has been around for a long time, but I think our results represent an important piece of the puzzle that mechanistically explains women’s increased risk as they age,” says Lipton.

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

(Only the title and image of this report may have been reworked by Business Standard staff; the rest of the content is automatically generated from the syndicated feed.)

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