Study shows why women are at higher risk of getting Alzheimer’s disease

In addition, we have shown how periodically occurring estrogen, whose synthesis declines during menopause, prevents the formation of this form of complement C3.

“Our new findings suggest that chemical modification of components of the complement system can help drive Alzheimer’s disease, and at least partially explain why the disease predominantly affects women. “Maybe.” He is a professor in the Department of Molecular Medicine at the Family Foundation-Endowed Scripps Research Institute and a clinical neurologist in La Jolla, California.

The research was a collaboration with a team led by Dr. Stephen Tanenbaum, a post-tenured Underwood Prescott Professor of Biotechnology, Chemistry and Toxicology at MIT.

Alzheimer’s disease is the most common form of dementia that occurs with age, currently afflicting about 6 million people in the United States alone.

It is always fatal, usually within 10 years of onset, and there are no approved treatments that can stop the progression of the disease.

The shortcomings of treatment reflect the fact that scientists do not fully understand how Alzheimer’s disease develops.

Scientists also don’t fully understand why women make up nearly two-thirds of cases.

Lipton’s lab studies biochemical and molecular events that may underlie neurodegenerative diseases, such as the chemical reaction that forms a modified form of complement C3, a process called protein S-nitrosylation. I’m here.

Lipton and his colleagues previously discovered this chemical reaction. This occurs when nitric oxide (NO)-related molecules bind tightly to sulfur atoms (S) on specific amino acid building blocks of proteins, forming modified ‘SNO proteins’. .

Protein modifications by small clusters of atoms such as NO are common in cells and typically activate or deactivate target protein function.

For technical reasons, S-nitrosylation has been more difficult to study than other protein modifications, but Lipton notes that the ‘SNO storm’ of these proteins is a major cause of Alzheimer’s disease and other neurodegenerative diseases. I think it is possible.

In a new study, researchers used a new method for detecting S-nitrosylation to quantify modified proteins in 40 postmortem human brains.

Half of the brains were from people who died with Alzheimer’s disease and half from people who didn’t, and each group was divided equally between men and women.

In these brains, scientists found 1,449 different proteins that are S-nitrosylated. Several proteins that are often modified in this way, such as complement C3, have already been linked to Alzheimer’s disease.

Strikingly, levels of S-nitrosylated C3 (SNO-C3) were more than six-fold higher in female Alzheimer’s disease brains compared to male Alzheimer’s disease 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 and cause inflammation in what is called the “complement cascade.”

It has been known for more than 30 years that Alzheimer’s disease brains have elevated levels of complement proteins and other inflammatory markers compared to neurologically normal brains.

More recent research has specifically shown that complement proteins can trigger resident brain immune cells called microglia to disrupt synapses, the connection points at which neurons signal to each other.

Many researchers now believe that this synaptic disruption mechanism underlies, at least in part, the Alzheimer’s disease process, and synaptic loss has been demonstrated to be significantly correlated with cognitive decline in the Alzheimer’s brain. I’m here.

The female hormone estrogen has long been proven to have protective effects on the brain under certain conditions. The researchers therefore 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 support this hypothesis and reveal that SNO-C3 increases as estrogen (b-estradiol) levels decrease due to activation of the enzyme that makes NO in brain cells. This increase in SNO-C3 activates synaptic disruption in microglia.

“Why women are more susceptible to Alzheimer’s disease has long been a mystery, but our results represent a key piece of the puzzle that mechanistically explains women’s increased vulnerability as they age. I think,” Lipton says.

He and his colleagues now want to conduct further experiments with denitrosylating compounds (which remove the SNO modification) to see if they can alleviate the pathology in animal models of Alzheimer’s disease and, ultimately, in humans. thinking about.