Neurodegenerative diseases, characterized by a progressive loss of brain function, mainly result from synaptic loss and neuronal cell death in the central nervous system. Alzheimer’s disease (AD) is perhaps the most common neurodegenerative disorder leading to dementia.
The shortcomings of treatments reflect that scientists have never fully understood how Alzheimer’s disease progresses. Scientists also don’t know why women account for nearly two-thirds of cases.
Researchers from MIT and Scripps Research have uncovered a clue to the molecular etiology of Alzheimer’s disease; this clue may also explain why women are more susceptible to the disease.
Researchers found that a particularly harmful, chemically modified form of an inflammatory immune protein called complement C3 was present in much higher concentrations 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 – generally protects against the production of this form of complement C3.
Study senior author Stuart Lipton, MD, Ph.D., professor and Step Family Foundation Endowed Chair in the Department of Molecular Medicine at Scripps Research and a clinical neurologist in La Jolla, California, said: “Our new findings suggest that chemical modification of a component of the complement system may help drive Alzheimer’s disease and may explain, at least in part, why the disease primarily affects women.”
Lipton’s lab is investigating biochemical and molecular processes, such as protein S-nitrosylation, that result in a modified version of complement C3, which may be the cause of neurodegenerative disorders. This chemical process, which produces a modified “SNO protein” when a nitric oxide (NO)-related molecule securely attaches to a sulfur atom (S) on a specific protein amino acid building block, was first discovered by Lipton and colleagues.
Small clusters of atoms, such as NO, often modify proteins in cells. These changes typically activate or inactivate the functions of a target protein. Due to technical difficulties, S-nitrosylation has received less attention than other protein modifications. Still, Lipton hypothesizes that the ‘SNO storms’ of these proteins may play an important role in the development of Alzheimer’s disease and other neurodegenerative diseases.
Lipton’s lab is investigating biochemical and molecular processes, such as protein S-nitrosylation, that result in a modified version of complement C3, which may be the cause of neurodegenerative disorders. This chemical process, which produces a modified “SNO protein” when a nitric oxide (NO)-related molecule attaches tightly to a sulfur atom (S) on a specific protein amino acid building block, was first discovered by Lipton and colleagues.
Small clusters of atoms, such as NO, often modify proteins in cells. These changes typically activate or inactivate the functions of a target protein. Due to technical difficulties, S-nitrosylation has received less attention than other protein modifications. Still, Lipton hypothesizes that the ‘SNO storms’ of these proteins may play an important role in the development of Alzheimer’s disease and other neurodegenerative diseases.
In the latest study, the scientists measured the amount of proteins changed in 40 postmortem human brains using brand new techniques for identifying S-nitrosylation. The brains were split equally between men and women, with half coming from individuals who had died of Alzheimer’s disease and the other half coming from people who hadn’t.
The researchers discovered 1,449 different proteins that were nitrosylated in this brain. Numerous proteins that have already been linked to Alzheimer’s disease were among those most frequently altered, including complement C3. Surprisingly, female Alzheimer’s brains had S-nitrosyl C3 (SNO-C3) levels more than six times higher than those of male Alzheimer’s brains.
The complement system is an evolutionarily older part of the human immune system. It consists of a family of proteins, including C3, that can activate each other to cause inflammation in the “complement cascade”.
For more than 30 years, researchers have known that, compared to neurologically healthy brains, Alzheimer’s brains exhibit higher amounts of complement proteins and other indicators of inflammation. In particular, more recent studies have shown how complement proteins can cause brain-resident immune cells known as microglia to break down synapses. Neurons communicate with each other at these junctions.
Many researchers now suspect that this synapse-destroying mechanism is partly at the root of Alzheimer’s disease. Loss of synapses has been shown to be a significant correlate of cognitive decline in the Alzheimer’s brain.
Why might female brains with Alzheimer’s have a higher prevalence of SNO-C3? The researchers hypothesized that estrogen protects women’s brains from C3 S-nitrosylation – and that this protection is lost when estrogen levels drop sharply with menopause. There has long been evidence that the female hormone estrogen can have brain-protective effects under certain circumstances. This theory was validated by experiments on cultured human brain cells, which showed that SNO-C3 increases as estrogen (-estradiol) levels fall due to activation of an enzyme that produces NO in brain cells. Synapses are destroyed by microglia when SNO-C3 levels rise.
Lipton says, “Why women are more likely to get Alzheimer’s has long been a mystery, but I think our results represent an important piece of the puzzle that mechanistically explains women’s increased vulnerability as they age.”
Magazine reference:
- Hongmei Yang, Chang-ki Oh, et al. Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3. Scientific progress. DOI: 10.1126/sciadv.ade0764
