In postmenopausal women, depletion of estrogen causes excessive elevation of nitric oxide in the brain and thus generates S-nitrosylated complement factor C3 (SNO-C3). SNO-C3 triggers activated microglial cells to phagocytose neuronal synapses. This aberrant chemical biology process results in synapse loss, leading to cognitive decline in Alzheimer’s disease. Credit: Chang-ki Oh and Stuart Lipton, Scripps Research
Key Points:
- An inflammatory immune protein called complement C3 may explain women’s increased risk for Alzheimer’s.
- Estrogen, which drops during menopause, normally protects against the creation of this form of C3.
- Future research will focus on reducing pathology in animal models of Alzheimer’s and eventually in humans.
Scientists at Scripps Research and MIT have found a clue to the molecular cause of Alzheimer’s, which may explain why women are at greater risk for the disease.
In the study published in Science Advances, 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 from the disease, compared with men. The team also showed that estrogen, which drops during menopause, normally protects against the creation of this form of C3.
“Our 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,” says study senior author Stuart Lipton, professor and chair at Scripps Research.
For the study, the researchers 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. 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, 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.
Researchers suspect this synapse-destroying mechanism at least partly underlies the Alzheimer’s disease process, and loss of synapses has been demonstrated to be a significant correlate of cognitive decline in Alzheimer’s brains.
The team now hopes to conduct further experiments with de-nitrosylating compounds to see if they can reduce pathology in animal models of Alzheimer’s, and eventually in humans.