Researchers at Scripps Research and MIT have discovered a potential biological reason for Alzheimer’s disease, which may also account for why women are at a higher risk of developing the condition.
The research, published on December 14, 2022 in Science Advances, discovered that the brains of women who had died from the condition had significantly higher concentrations of a chemically modified type of an inflammatory immune protein called complement C3 than those of males who had died from the disease. They also discovered that estrogen, the synthesis of which declines after menopause, generally serves as a barrier to the formation of this particular type of complement C3.
Research senior author Stuart Lipton, MD, PhD, 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 the new findings highlight that chemical modification of a constituent of the complement system helps influence Alzheimer’s, and may clarify, why the illness primarily affects women.
In this work, MIT’s Post Tenure Underwood-Prescott Professor of Biological Engineering, Chemistry, and Toxicology Steven Tannenbaum and his colleagues participated.
About 6 million people in the United States alone are dealing with Alzheimer’s disease, the most prevalent form of dementia associated with aging. There is currently no cure or even medication that can slow the progression of the disease, and it is usually deadly within a decade of onset. The fact that scientists still don’t have a full picture of Alzheimer’s disease progression explains why medications fall short. There is a gender disparity in this disease, with women making up approximately two-thirds of all cases, although the exact reason for this is unknown.
The chemical reaction that produces a modified version of complement C3, a process known as protein S-nitrosylation, is one of several biochemical and molecular processes studied at Lipton’s lab as potential causes of neurodegenerative disorders. An “SNO-protein” is formed when a nitric oxide (NO)-related molecule attaches strongly to a sulfur atom (S) on a specific amino acid building block of proteins; this reaction was previously found by Lipton and his coworkers. Modifications of proteins by atomic clusters, such as NO, are widespread in cells and can either stimulate or inhibit the protein’s normal activity. While S-nitrosylation has been less studied than other protein modifications due to technological limitations, Lipton believes that “SNO-storms” of these proteins may be a major factor in Alzheimer’s disease and other neurodegenerative illnesses.
Researchers in the current study employed cutting-edge techniques for identifying S-nitrosylation to determine the exact number of proteins that had been altered in the brains of 40 people who had passed away. Males and females made up an equal number of brains from both the Alzheimer’s disease and non-disease Alzheimer’s groups.
A total of 1,449 unique S-nitrosylated proteins were identified in these brains. Several proteins, notably complement C3, have been previously linked to Alzheimer’s disease, and were among the most frequently changed proteins. More than six times as much S-nitrosylated C3 (SNO-C3) was found in female Alzheimer’s brains compared to male Alzheimer’s brains.
The human immune system’s complement system has been around for quite some time. The complement cascade is a group of proteins, including C3, that can cross-activate to promote inflammation. Alzheimer’s disease is associated with increased levels of complement proteins and other signs of inflammation, which have been known for over 30 years by scientists to be present in the brains of people with the disease compared to those with normal neurological function. Recent studies have revealed that some complement proteins can directly cause microglia, brain-resident immune cells, to damage synapses, the junctions between neurons that allow them to communicate with one another. Loss of synapses has been shown to be a major predictor of cognitive impairment in Alzheimer’s disease brains, leading many researchers to believe that this synapse-destroying mechanism at least partly explains the Alzheimer’s disease process.
Why is SNO-C3 more prevalent in Alzheimer’s disease of female brains? Since estrogen has been shown to protect the brain in certain situations, the researchers postulated that estrogen particularly protects the brains of women from C3 S-nitrosylation, and that this defense is lost when estrogen levels fall dramatically, as they do after menopause. Human brain cell cultures validated this theory by showing that NO-producing enzyme activation causes SNO-C3 to rise in response to declining estrogen (-estradiol) levels. This upregulation of SNO-C3 causes microglia to initiate the destructive process of synapses.
Why women are more vulnerable to Alzheimer’s as they age is a mystery that has existed for a long time, but the data constitute an essential piece of the jigsaw.
In order to determine if de-nitrosylating chemicals (those that eliminate the SNO alteration) can relieve Alzheimer’s disease pathology in animal models and, eventually, people, the researchers want to perform more tests.
Yang, H., Oh, C. K., Amal, H., Wishnok, J. S., Lewis, S., Schahrer, E., Trudler, D., Nakamura, T., Tannenbaum, S. R., & Lipton, S. A. (2022). Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3. Science advances, 8 (50), eade0764. https://doi.org/10.1126/sciadv.ade0764