Study Links Gene to Cognitive Resilience in Older Adults | MIT News

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Many people develop Alzheimer’s disease or other forms of dementia as they age. However, others remain alive into old age, even if their brains show underlying signs of neurodegeneration.

Among these cognitively resilient individuals, researchers have identified level of education and time spent in intellectually stimulating activities as factors that help prevent dementia. A new study by researchers at MIT shows that this type of enrichment appears to activate a family of genes called MEF2, which controls a genetic program in the brain that promotes resistance to cognitive decline.

Researchers observed this link between MEF2 and cognitive resilience in humans and mice. The results suggest that enhancing the activity of MEF2 or its targets could protect against age-related dementia.

“There is growing recognition that there are resiliency factors that can protect brain function,” says Li-Huei Tsai, director of the Picower Institute for Learning and Memory at MIT. “Understanding this mechanism of resilience could be useful when we think of therapeutic interventions or prevention of cognitive decline and dementia associated with neurodegeneration. “

Tsai is the lead author of the study, which appears today in Science Translational Medicine. The lead authors are Scarlett Barker, a recent MIT PhD recipient, and MIT postdoctoral fellow and Boston Children’s Hospital physician Ravikiran (Ravi) Raju.

Protective effects

Much research suggests that environmental stimulation offers some protection against the effects of neurodegeneration. Studies have linked education level, type of job, number of languages ​​spoken, and time spent on activities such as reading and crossword puzzles to higher degrees of cognitive resilience.

The MIT team tried to understand how these environmental factors affect the brain at the neuronal level. They looked at human data sets and mouse models in parallel, and the two leads converged on MEF2 as a key player.

MEF2 is a transcription factor that was originally identified as an important factor in the development of heart muscle, but was later found to play a role in neural function and neurodevelopment. In two human datasets comprising just over 1,000 people in total, the MIT team found that cognitive resilience was strongly correlated with expression of MEF2 and many of the genes it regulates.

Many of these genes code for ion channels, which control a neuron’s excitability, or how easily it triggers an electrical impulse. The researchers also found, from a single-cell RNA sequencing study of human brain cells, that MEF2 appears to be most active in a subpopulation of excitatory neurons in the prefrontal cortex of resilient individuals.

To study cognitive resilience in mice, the researchers compared mice raised in cages without toys and mice placed in a more stimulating environment with a wheel and toys exchanged every few days. As they discovered in the human study, MEF2 was more active in the brains of mice exposed to the enriched environment. These mice also performed better in learning and memory tasks.

When the researchers turned off the MEF2 gene in the frontal cortex, it blocked the mice’s ability to benefit from breeding in an enriched environment, and their neurons became unusually excitable.

“This was particularly exciting because it suggested that MEF2 plays a role in determining overall cognitive potential in response to environmental variables,” Raju said.

The researchers then explored whether MEF2 could reverse some of the symptoms of cognitive impairment in a mouse model that expresses a version of the tau protein that can form tangles in the brain and is linked to dementia. While these mice were designed to overexpress MEF2 at a young age, they did not show the usual cognitive impairments produced by the tau protein later in life. In these mice, neurons overexpressing MEF2 were less excitable.

“Numerous studies in humans and in mouse models of neurodegeneration have shown that neurons become hyperexcitable in the early stages of disease progression,” says Raju. “When we overexpressed MEF2 in a mouse model of neurodegeneration, we saw that it was able to prevent this hyperexcitability, which might explain why they performed better cognitive results than control mice.”

Improve resilience

The results suggest that enhancing MEF2 activity may help protect against dementia; However, since MEF2 also affects other cell types and cellular processes, more studies are needed to ensure that its activation does not have unwanted side effects, the researchers said.

The MIT team now hopes to study in more detail how MEF2 is activated by exposure to a nurturing environment. They also plan to examine some of the effects of other genes controlled by MEF2, beyond the ion channels they explored in this study. Such studies could help reveal additional targets for drug treatments.

“You could potentially imagine a more targeted therapy by identifying a subset or class of effectors that is critically important to induce resilience and neuroprotection,” says Raju.

The research was funded by the Glenn Center for Biology of Aging Research, the National Institute of Aging, the Cure Alzheimer’s Fund, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.


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