Protein Modifications May Explain Why More Women Get Alzheimer’s Disease

A new study has discovered that a modified immune system protein is more common in women with Alzheimer’s disease (AD) than men, providing a molecular clue as to why women are at a higher risk of AD. The research is published in Science Advances.

Women have a higher risk of AD

AD is the most common form of dementia, a progressive syndrome associated with aging that leads to declines in cognitive functioning and accounts for 60–70% of dementia cases. Memory, reasoning and comprehension are all affected, commonly occurring alongside shifts in mood, personality and behavior.

The precise process by which AD develops is not fully understood, but it is characterized by the aggregation of misfolded amyloid-β proteins, abnormal tangles of tau proteins and the loss of neural connections (synapses) that are associated with cognitive decline. However, there are no effective treatments available to prevent the progression of AD. Of the  ~6 million Americans that have AD, almost two-thirds are women, though scientists remain unsure of exactly why this is the case.

In a previous study, researchers studied a protein modification process called S-nitrosylation (SNO) that can modify a protein’s function. These so-called “SNO-proteins” have been implicated in the development of several neurodegenerative diseases.

In the current study, the researchers investigated the appearance of SNO-proteins in post-mortem brain samples of patients with and without AD, discovering sex-dependent differences in the appearance of SNO-proteins in those with the disease.

Could a fall in estrogen be to blame?

The researchers examined post-mortem brain samples from 20 patients that died from AD and 20 that had not, with an equal number of males and females per group. Across the cohort, they analyzed the presence and abundance of SNO-proteins, identifying almost 1,500 different types. They discovered that the addition of SNO to an immune system protein called complement C3 occurred more often in the brains of women with AD than men. C3 functions as part of the innate immune system called the complement cascade, which is known to be elevated in AD brain tissue and promotes inflammation. The complement cascade can trigger the brain’s resident immune cells – microglia – to destroy synapses, the vital signaling and connection points between neurons.

Investigating why the brains of women with AD had such elevated levels of SNO-C3 compared to men, the researchers hypothesized that there may be a link to the loss of estrogen – and its associated brain-protective properties – after menopause. Experiments with lab-cultured brain cells confirmed that as estrogen levels fall there is a subsequent increase in SNO-C3 levels, which triggers the destruction of synapses by microglia. This was a key finding, given the correlation between synaptic loss and cognitive decline in AD.

“Lots of prior work had indicated that estrogen might be involved in neurodegenerative diseases such as Alzheimer’s, and inflammation had also been linked to disorders,” explained Stuart Lipton, professor of neuroscience at Scripps Research and senior author of the study. “We put two and two together and identified one of the major players in the process – that is SNO-C3.”

A possible piece of the AD puzzle

Nevertheless, Lipton expanded on some of the study’s limitations: “We looked at post-mortem human brains, not living brains, so although we are confident of the changes we found, we do not know exactly at what stage of the disease they develop. Nonetheless, our human stem cell-derived model system shows that SNO-C3 can participate in injuring the synaptic connections between nerve cells, arguably the best correlate with cognitive decline in Alzheimer’s and other dementias.”

The authors explained that, overall, these findings may provide clues to help solve the mystery of why women are more likely to develop AD. Next, they are planning further experiments to test whether compounds that remove the SNO modifications could have a beneficial effect in animal models of AD.

Reference: Yang H, Oh C, Amal H, Wishnok JS, et al. Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3. Sci Adv. 2022. doi: 10.1126/sciadv.ade0764

Prof. Stuart Lipton was speaking to Sarah Whelan, Science Writer for Technology Networks.