Mouse model suggests why women are more prone to Alzheimer's

Scientists from Nanyang Technological University, Singapore (NTU Singapore) and the National University of Singapore (NUS) have examined why, in mice, female brains are more predisposed to Alzheimer’s disease and other neurodegenerative diseases.

The team’s study, published in the journal Aging Cell, sought to identify some of the molecular mechanisms in memory formation and the progression of Alzheimer’s disease between both sexes. It is well documented that Alzheimer’s disproportionately affects more women than men, and for a long time scientists thought this was because women on average live longer than men, but the study based on mice models provided evidence that this was not the case.

The team’s lab experiments revealed that female mice with mutations associated with Alzheimer’s disease had a faster decline in long-term potentiation (LTP) compared to the mutant male mice. LTP in the hippocampus is the process by which synaptic strength is increased between neurons that form long-term memories, making it one of the major cellular mechanisms guiding how the brain forms memories and learns new things.

The scientists stimulated mice brain samples which had Alzheimer’s mutations using electricity and recorded the resulting brain waves and activity. In a series of experiments, the scientists showed that the memory formation through LTP tends to decay faster in female mice bred to be more susceptible to Alzheimer’s compared to males.

“In the model, if LTP remains strong over a long period of time, it indicates that a memory is stable,” said study co-leader Assistant Professor Ch’ng Toh Hean, from NTU. “If it decays over time, then the memory is lost. The correlation we drew here is that by seeing rapid decay in LTP, the memory is corrupted and weakened, much like what happens in an Alzheimer’s patient.”

In one experiment, the scientists induced LTP in mice using strong tetanic stimulation (STET) — a high-frequency burst that stimulates the brain’s neurons. They found that a STET-induced LTP lasted for 180 minutes in Alzheimer-susceptible males, but only 95 minutes in females. Similarly, a theta burst stimulation-induced LTP lasted 90 minutes in male mice, and 70 minutes for female mice.

“Faster LTP decline in female mice lends credence to the idea that there is strong robust difference between the sexes,” Asst Prof Ch’ng said.

Analysis of brain sections also showed that female mice with Alzheimer’s disease have increased markers of inflammation, which could explain why there is greater deterioration of LTP in female mice. Indeed, the brains of female mice with the Alzheimer’s genetic mutation were deemed by the researchers to be less flexible, or ‘plastic’, in adapting to new information and forming new memories.

“Our results showed that a stronger inflammatory response, coupled with weaker plasticity in the hippocampus of Alzheimer’s disease females, could explain why there is faster memory decline in Alzheimer’s females compared with males,” said NTU senior research fellow Dr Sheeja Navakkode, first author on the paper.

“Studying Alzheimer’s in genetically modified mice is useful as they model different aspects of the disease. This is particularly true when investigating cell and molecular pathways in the brain that are similar in humans and mice.”

Asst Prof Ch’ng added, “As diminished synaptic function is an early event of Alzheimer’s disease, strategies to detect early decay of memory may help alert patients to the onset of such neurodegenerative diseases. While the impact of hormones on Alzheimer’s disease remains to be clarified, altered brain hormone levels may yet provide clues in understanding how weakened neural plasticity and memory loss differ among the sexes.”

While the team’s study presents evidence that Alzheimer’s disease mutations result in greater deterioration of brain plasticity in female mice brains compared to male mice brains, further research is required to understand the molecular basis behind this.

“Studying how gender contributes to differences in disease progression will help with understanding the overall causes of Alzheimer’s disease,” Assoc Prof Sreedharan Sajikumar said. “It shows the vital importance of the need to include gender as a biological variable in all biomedical research, as females and males have distinct differences in disease progression.”

Image credit: ©stock.adobe.com/au/pathdoc

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