Why does Alzheimer's disease "prefer" women? Perhaps related to complement C3

Scientists at Scripps Research Institute and the Massachusetts Institute of Technology have discovered a new clue about Alzheimer's disease — a clue that may explain why women are at higher risk for the disease
.

The researchers wrote in the journal Science Advances that women who died of Alzheimer's disease had higher levels of harmful protein, chemically modified complement C3
, in their brains compared to men.
They also showed that estrogen normally prevents the production of this complement C3, but estrogen drops
dramatically during menopause.

Co-corresponding author Stuart Lipton, a professor in the Department of Molecular Medicine at the Scripps Institute, said: "Our new findings suggest that chemical modifications of individual components of the complement system contribute to Alzheimer's disease and partly explain why the disease mainly affects women
.
"The study was carried out
in collaboration with a team led by Professor Steven Tannenbaum of MIT.

Alzheimer's disease (AD) is the most common form of dementia and usually affects people
over the age of 65.
Over time, brain problems can get worse
.
There is currently no treatment that can stop the disease from progressing, let alone reverse it
.
It also reflects the fact that scientists never fully understood how Alzheimer's disease progresses
.
They also don't know why women account for nearly two-thirds
of patients.

Professor Lipton's team investigated various biochemical and molecular events that can lead to neurodegenerative diseases, including modification of complement C3, a process known as protein S-nitrosylation
.
Lipton and colleagues previously discovered this chemical reaction, which refers to nitric oxide (NO)-related molecules tightly binding to sulfur atoms (S) on specific amino acids to form modified "SNO proteins.
"

Proteins modified by small molecules, such as NO, are common in cells and often activate or inactivate
the function of the target protein.
S-nitrosoation is harder to study than other protein modifications for technical reasons, but Lipton suspects that the "SNO storm" of these proteins may be a key cause
of Alzheimer's disease and other neurodegenerative diseases.

In the new study, the researchers used a new method to detect S-nitrosylation to quantify proteins
in 40 autopsy human brain samples.
Half of the sample was from Alzheimer's patients and the other half from non-Alzheimer's patients, with men and women in each group divided equally
.

In these samples, the researchers found 1449 proteins
modified by S-nitrosylation.
Among the proteins most commonly modified in this way, several are associated with Alzheimer's disease, including complement C3
.
Notably, female 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 evolutionary part of
the human immune system.
It consists of a series of proteins, including C3, that activate each other and trigger inflammation, which is known as the "complement cascade.
"
Scientists have known for more than 30 years that Alzheimer's patients have higher levels of complement protein and other inflammatory markers in their brains than normal
brains.

Recent studies have shown that complement proteins can trigger microglia to disrupt synapses, the connection points
where neurons send signals to each other.
Many researchers suspect that this synapse-disrupting mechanism has at least partly triggered Alzheimer's disease, and the loss of synapses has proven to be an important correlation factor
in cognitive decline in Alzheimer's brains.

So why is SNO-C3 more common in the brains of women with Alzheimer's? There has long been evidence that estrogen can protect the brain in certain situations; Therefore, the researchers hypothesized that estrogen protected women's brains from C3 S-nitrosylation — a protection that is lost
when estrogen levels drop dramatically during menopause.

Experiments on cultured brain cells also supported this hypothesis, showing that SNO-C3 increased as estrogen levels declined, due to the activation
of NO-producing enzymes in brain cells.
The increase in SNO-C3 activates the destruction
of synapses by microglia.

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

The researchers plan to conduct further experiments using compounds that remove SNO modifications to see if they can reduce pathological symptoms in animal models of Alzheimer's disease and ultimately improve symptoms
in humans.

Original search

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