A New Discovery Regarding The Molecular Cause Of Alzheimer’s Disease Might Explain Why Women Are Disproportionately Affected
Over 6 million Americans ages 65 and older are currently living with Alzheimer’s disease (AD).
But, women specifically make up two-thirds of this figure– with a woman’s estimated lifetime risk of developing AD at 65 years old being just one in five, according to the Alzheimer’s Association.
While it has long been known that women disproportionately represent the majority of AD diagnoses– a disease that is fatal and which currently has no approved treatments to halt its progression– scientists have not understood why women are especially at risk.
Recently, though, a new study conducted by researchers at the Massachusetts Institute of Technology (MIT) and Scripps Research has uncovered one molecular clue.
The study, published just two weeks ago in Science Advances, revealed that women who died from AD had much higher levels of a harmful and chemically modified inflammatory immune protein, known as complement C3, in their brains as compared to men.
It was also found that estrogen, a hormone that typically drops off in production during menopause, usually protects against the creation of this complement C3 form.
So, the research teams’ findings essentially suggest that a chemical modification of the complement system is a driving risk factor for AD– which begins to explain why the disease predominantly affects older women.
The study was led by Stuart Lipton, MD, Ph.D., who is a professor, chairman of the Scripps Research Department of Molecular Medicine, and a clinical neurologist based in La Jolla, California.
Lipton’s lab, which specifically studies the molecular and biochemical events that are behind neurodegenerative diseases, spearheaded this effort.
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In the past, his team specifically analyzed the chemical reaction– a process known as protein S-nitrosylation– that ultimately forms the modified form of complement C3.
The process essentially begins when a nitric oxide (NO) molecule tightly binds to a sulfur atom (S) on one distinct amino acid building block to create a modified “SNO-protein” form.
Now, within cells, it is common for small clusters of atoms– like NO– to undergo protein modifications. These changes usually work to activate or deactivate the function of a target protein.
However, Lipton suspected that these modifications– coined as “SNO-storms”– might be a critical contributor to the development of Alzheimer’s as well as other neurodegenerative disorders.
So, for his most recent study, Lipton and his team utilized novel S-nitrosylation detection techniques to quantify the number of modified proteins in the brains of forty deceased individuals.
Half of the individuals had died of AD, and the other half did not. Each group was also segmented equally between males and females.
The scientists found that over 1,400 different proteins had been S-nitrosylated within these brains.
Most notably, though, the presence of S-nitrosylated C3 (SNO-C3) was found to be over 600% higher among females who died of AD as opposed to males who died of AD.
It has been known for over three decades that the brains of Alzheimer’s patients contain higher levels of complement proteins, as well as other inflammation markers.
However, research in recent years has shown that complement proteins can actually trigger immune cells in the brain– known as microglia– to destroy synapses.
In other words, the neural network connection points that neurons use to communicate via signals.
In turn, numerous scientists now believe that this synapse destruction may be at least one contributing factor to the onset of AD– especially since synapse loss has been tied to cognitive decline in AD brains.
As for why female brains are more susceptible to SNO-C3, Lipton and his team believe this is due to the female hormone estrogen. Countless past studies have found estrogen to have a brain-protecting effect under certain conditions.
So, the researchers believe that estrogen protects women from C3 S-nitrosylation during the earlier stages of life. Then, after estrogen levels fall significantly during menopause, the protection is lost.
Experiments using cultured human brain cells also supported this belief, showing that as estrogen levels decrease, SNO-C3 increases. Then, this increase subsequently activates the destruction of neural synapses.
“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 the increased vulnerability of women as they age,” Lipton said.
Now, he and his team are eager to conduct additional experiments centered around de-nitrosylating compounds– or compounds that remove SNO modification– in order to reduce pathology first in animal models of AD and then eventually in human AD brains.
To read the study’s complete findings, which have since been published in Science Advances, visit the link here.
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