Menopause may increase Alzheimer’s risk – Science et Avenir

Alzheimer’s disease affects about a million people in France each year, 60% of whom are women. according to Inserm. This gap between the sexes is partly due to the difference in life expectancy (they have more). But biological factors such as hormones may also play a role. Specifically, estrogen, which would have protected women’s brains in the first half of their lives, but whose fall during menopause would have made them more vulnerable. New study published December 14, 2022 in the journal Scientific achievementssupports this hypothesis by showing that the brains of women with Alzheimer’s disease have higher levels of a pro-inflammatory protein associated with the development of this disease than those of men with Alzheimer’s disease, and that the level of this protein depends on estrogen levels.

Search for modified proteins in the brains of people with Alzheimer’s disease

Researchers from the Massachusetts Institute of Technology, the Scripps Research Institute at La Jolla and the University of California at San Diego (USA) compared the brains of 40 people who died and had or did not suffer from this disease (more men than women over 70). . Samples of their frontal cortex were analyzed for the presence of proteins with a specific modification: S-nitrolization, when a nitric oxide group is added to the protein. Why this particular change? Because these researchers already allocated in 2016 that the accumulation of beta-amyloid peptide (involved in the occurrence of Alzheimer’s disease) causes disturbances in this process, leading to the destruction of synapses in Alzheimer’s disease.

A protein more modified in women than in men

A total of 1,450 proteins showed this modification, including 40% in the brains of people with Alzheimer’s alone. Among proteins altered only in sick people, differences were noted between the brains of men and women. Including pro-inflammatory proteins, including the C3 protein, which is part of the innate immune system. In the brains of women with the condition, levels of this modified protein were 30 times higher than in women who died from other causes (compared to a 5-fold increase in men).

C3 is part of the complement system, a group of proteins that stimulate inflammation during infection and destroy pathogens. In addition to fighting infection, the complement system helps glial cells in the brain eliminate redundant synapses (connections between neurons) during neuronal development. This is how the C3 protein can accelerate the onset of Alzheimer’s disease. Indeed, the researchers demonstrated that a modified version of C3 caused glial cells to destroy more synapses.

Estrogen prevents modification of the C3 protein.

It is known that estradiol, an essential estrogen in women, can prevent S-nitrolization in glial cells by blocking the production of nitric oxide, the main ingredient in this process. The researchers wanted to make sure that this was indeed the case with the C3 protein as well. Indeed, the addition of this hormone to the culture medium of human glial cells avoids C3 S-nitrolysis in the presence of beta-amyloid peptide. Whereas without estradiol, beta-amyloid induced this modification of C3.

A result that suggests that estrogen protects the brains of pre-menopausal women by preventing abnormalities in C3 and therefore in the complement system that can lead to excessive inflammation. On the other hand, this protection will disappear when this hormone drops after menopause, which will increase their risk of developing Alzheimer’s disease. “I think our findings are an important piece of the puzzle as to why women become more vulnerable to this condition as they age,” said Stuart Lipton, a neuroscientist at the Scripps Research Institute and leader of the study.

These results need to be confirmed because this study is based solely on the brains of ten women who died of Alzheimer’s disease. But if they are confirmed, they will confirm the importance of hormones in the development of neurodegenerative diseases, highlighting The therapeutic role that hormone treatment may have for postmenopausal women.

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