New findings from Science Advances could explain why women are more likely to develop Alzheimer's

Scientists at the Scripps Institute and the Massachusetts Institute of Technology (MIT) have found clues to the molecular causes of Alzheimer's disease — a clue that could also explain why women are at higher risk for the disease
.

The researchers found that women who died of Alzheimer's disease had much higher levels of complement, a particularly harmful, chemically modified inflammatory immune protein, in their brains compared to men who died of Alzheimer's disease
.
They also showed that estrogen — produced during menopause — generally prevents the production
of this form of complement C3.

"Our new findings suggest that chemical modifications of one component of the complement system contribute to Alzheimer's disease and may explain, at least in part, why the disease primarily affects women.
"

Alzheimer's is the most common dementia that occurs with age, currently affecting about 6 million people in the United States alone
.
It is always fatal, usually within a decade of onset, and there are currently no approved treatments that can stop the progression of the disease, let alone reverse it
.
The flaws in the treatment reflect the fact that scientists never fully understood how Alzheimer's disease progresses
.
Scientists also don't entirely know why women account for nearly two-thirds of cases
.

This laboratory study could lead to biochemical and molecular events in neurodegenerative diseases, including a chemical reaction that forms a modified complement C3, a process
called protein S-nitrosylation.
Lipton and his colleagues previously discovered this chemical reaction, which occurs
when a nitric oxide (NO)-related molecule tightly binds to sulfur atoms (S) on the amino acid building blocks of a particular protein to form a modified "sno protein.
" Proteins modified by small atomic clusters, such as NO, are common in cells and often activate or fail the function of
the target protein.
S-nitrosoylation is harder to study than other protein modifications for technical reasons, but Lipton suspects that the "sno storm" of these proteins could be a key factor
in Alzheimer's and other neurodegenerative diseases.

In the new study, the researchers used a new method to detect S-nitrosylation to quantify the modified proteins
in the brains of 40 postmortem humans.
Half of the brains came from people who died of Alzheimer's and the other half from people who didn't — divided equally between men and women in each group
.

In these brains, the scientists found 1449 different proteins
that were S-nitrosylated.
Among the proteins most often modified in this way, several have been linked to Alzheimer's disease, including complement C3
.
Strikingly, female Alzheimer's patients had more than 6 times higher levels of s-nitrosylated C3 (SNO-C3) in their
brains compared to men.

The complement system is an earlier evolved part
of the human immune system.
It consists of a series of proteins, including C3, that activate each other, triggering inflammation, which is known as the "complement cascade.
"
Scientists have known for more than 30 years that Alzheimer's brains have higher levels of complement proteins and other inflammatory markers than neurologically normal
brains.
Recent studies in particular have shown that complement proteins can trigger resident brain immune cells called microglia to disrupt synapses — the connection points
between neurons that transmit signals.
Many researchers now suspect that this mechanism of disrupting synapses is at least partly responsible for the Alzheimer's process, and that the loss of synapses has proven to be an important correlated factor
in cognitive decline in Alzheimer's brains.

Why is SNO-C3 more common in the brains of women with Alzheimer's? There has long been evidence that the female hormone estrogen can play a role in protecting the brain in certain situations; Therefore, the researchers hypothesized that estrogen could specifically protect women's brains from C3s-nitrosylation — a protection that is lost
when estrogen levels drop dramatically with menopause.
Experiments with cultured human brain cells supported this hypothesis, showing that SNO-C3 increased as estrogen (β-estradiol) levels decreased, due to the activation
of an enzyme in brain cells that produces NO.
The increase in SNO-C3 activates microglial destruction
at synapses.

"Why women are more likely to develop Alzheimer's has always been a mystery, but I think our findings represent an important part of the puzzle, mechanically explaining why women are more susceptible as they age
," Lipton said.

He and his colleagues now hope to conduct further experiments with denitrosylated compounds (removal of SNO modifications) to see if they can reduce pathologies in animal models of Alzheimer's and, ultimately, in humans
.