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News and Research: Study on why women are more likely to get Alzheimer’s

Article: Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3 Science Advances, Dec. 2022

Overview: The question of why women are at a much higher risk than men for Alzheimer’s has puzzled researchers for a while. And no, the increased risk is not entirely explained by women living longer than men.

Funded by the NIH, researchers from MIT and the Scripps Institute investigated the brains of Alzheimer’s patients vs. healthy controls. They investigated how post-translational changes were different in Alzheimer’s, and how those changes were influenced by alterations in estrogen levels after menopause.

S-nitrosylation is one way proteins can be modified after they have been translated. Nitric oxide is a reactive molecule formed from arginine and is quickly used in cellular reactions. It can act as an antioxidant, or, in the presence of increased ROS, it can form strong oxidants.[ref]

The researchers found increased S-nitrosylation in pathways related to the pathogenesis of Alzheimer’s. The researchers also found differences in S-nitrosylation of proteins in male vs. female Alzheimer’s brains — and differences from healthy brains.

One particularly intriguing finding:

“Complement factor C3, which plays a pivotal role in the innate immune system (51), was among the most abundant S-nitrosylated proteins in AD brains. C3 has previously been linked to AD pathology (5253) but was not recognized to be S-nitrosylated or to be distributed in a sex-specific manner. In our SNO protein datasets, we observed a significant increase in SNO-C3 in female AD brains, exhibiting a 34.2-fold increase over female non-AD control brains ”

The researchers conclude: “Accordingly, we hypothesized that menopause-associated up-regulation of inflammation in the brain could be causally linked to the aberrant increase in SNO-C3 that we observed. Together with prior findings, we found evidence that a drop in β-estradiol levels leads to increased iNOS expression, thus contribution to SNO-C3 production. Thus, dysregulation of the complement system may play a role in the pathogenesis of AD and explain, at least in part, the female predominance of the disease”


Related studies that add context:

Targeted metabolomic analysis of nitric oxide/L-arginine pathway metabolites in dementia: association with pathology, severity, and structural brain changes

Complement C3 Is Activated in Human AD Brain and Is Required for Neurodegeneration in Mouse Models of Amyloidosis and Tauopathy 

About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering from Colorado School of Mines and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.