Alzheimer’s, the most common form of dementia that occurs with aging, currently afflicts about six million people in the U.S. alone.
It is always fatal, usually within a decade of onset.
In a study from Scripps Research and Massachusetts Institute of Technology, scientists found a clue to the molecular cause of Alzheimer’s—a clue that may also explain why women are at greater risk for the disease.
The researchers found that a particularly harmful, chemically modified form of an inflammatory immune protein called complement C3 was present at much higher levels in the brains of women who had died of the disease, compared to men who had died of the disease.
They also showed that estrogen—which drops in production during menopause—normally protects against the creation of this form of complement C3.
The new findings suggest that chemical modification of a component of the complement system helps drive Alzheimer’s, and may explain, at least in part, why the disease predominantly affects women.
In the study, the team used novel methods for detecting S-nitrosylation to quantify proteins modified in 40 postmortem human brains.
Half of the brains were from people who had died of Alzheimer’s, and half were from people who hadn’t—and each group was divided equally 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, there were several that have already been tied to Alzheimer’s, including complement C3.
Strikingly, the levels of S-nitrosylated C3 (SNO-C3) were more than six-fold higher in female Alzheimer’s brains compared to male Alzheimer’s brains.
Why would SNO-C3 be more common in female brains with Alzheimer’s? There has long been evidence that the female hormone estrogen can have brain-protective effects under some conditions.
The researchers hypothesized that estrogen specifically protects women’s brains from C3 S-nitrosylation—and this protection is lost when estrogen levels fall sharply with menopause.
Experiments with cultured human brain cells supported this hypothesis, revealing that SNO-C3 increases as estrogen (β-estradiol) levels fall, due to the activation of an enzyme that makes NO in brain cells.
This increase in SNO-C3 activates microglial destruction of synapses.
The researchers now hope to conduct further experiments with de-nitrosylating compounds—which remove the SNO modification—to see if they can reduce pathology in animal models of Alzheimer’s and eventually in humans.
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The study was conducted by Stuart Lipton et al and published in Science Advances.
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