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 etiology and pathogenesis of AD are incompletely understood and effective, disease-modifying drug treatments are lacking.

Previous work has shown that genetic, environmental, and age-related factors, along with changes in energy metabolism, autophagy, and synaptic function, all contribute to the pathogenesis of AD. A new study by scientists at Scripps Research and the Massachusetts Institute of Technology (MIT) has found a clue to the molecular cause of Alzheimer’s disease. This clue may also explain why women are at greater risk for the disease.

Scientists found that the brains of women who had died of the condition contained significantly higher levels of complement C3, a dangerous inflammatory response protein that has undergone chemical modification. In addition, they showed that estrogen typically protects against the formation of this type 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 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 an altered 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 modifications typically activate or deactivate 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 number 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 scientists found 1,449 different proteins that were S-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 older part of the human immune system in terms of evolution. The “complement cascade” consists of a family of proteins, including C3, that can activate each other to cause inflammation. For more than 30 years, scientists have known that Alzheimer’s brains, compared to neurologically healthy 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. Loss of synapses is a substantial link to cognitive decline in Alzheimer’s disease, and many scientists now believe that this synapse-destroying mechanism is at least partially driving the disease process.

Why might female brains with Alzheimer’s have a higher prevalence of SNO-C3? The scientists hypothesized that estrogen explicitly 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. This rise in SNO-C3 causes the breakdown of synapses by microglia.

Study senior author Stuart Lipton, MD, Ph.D., said: “Why women are more likely to get Alzheimer’s disease 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.”

“Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3.”

Magazine reference:

  1. Hongmei Yang 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