Many people develop Alzheimer’s or other forms of dementia as they get older. Others, however, remain sharp into old age, even if their brains show underlying signs of neurodegeneration.
Among these cognitively resilient people, researchers have identified the level of education and the time they devote to intellectually stimulating activities as factors that help prevent dementia. A new study by MIT researchers shows that this type of accumulation appears to activate a family of genes called MEF2, which controls a genetic program in the brain that promotes resistance to cognitive decline.
The researchers observed this connection between MEF2 and cognitive endurance in both humans and mice. The results suggest that enhancing the activity of MEF2 or its targets might protect against age-related dementia.
“There is a growing understanding that there are resilience factors that can protect brain function,” says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory. “Understanding this resilience mechanism could be helpful when we think about therapeutic interventions or the prevention of cognitive decline and neurodegeneration-related dementia.”
Tsai is the senior author of the study, which appears today in Science Translational Medicine. The lead authors are recent MIT graduate student Scarlett Barker and MIT postdoctoral fellow and Boston Children’s Hospital Physician Ravikiran (Ravi) Raju.
A large body of research suggests that environmental stimulation provides some protection against the effects of neurodegeneration. Studies have linked educational level, type of job, number of languages spoken, and time spent on activities like reading and crossword puzzles to higher levels of cognitive resilience.
The MIT team tried to figure out how these environmental factors affect the brain at the neural level. They looked at human datasets and mouse models in parallel, and both tracks converged on MEF2 as the critical actor.
MEF2 is a transcription factor that was originally identified as an important factor in heart muscle development, but was later discovered to play a role in neuron function and neurodevelopment. In two human datasets totaling just over 1,000 people, the MIT team found that cognitive endurance was strongly correlated with the expression of MEF2 and many of the genes it regulates.
Many of these genes encode ion channels, which control a neuron’s excitability, or how easily it fires 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 examine cognitive resilience in mice, the researchers compared mice raised in cages without toys and mice housed in a more stimulating environment with an exercise wheel and toys that were rotated every few days. As they found in the human study, MEF2 was more active in the brains of the mice exposed to the enriched environment. These mice also performed better on learning and memory tasks.
When the researchers knocked out the gene for MEF2 in the frontal cortex, it blocked the mice’s ability to benefit from rearing in the enriched environment, and their neurons became abnormally excitable.
“This was particularly exciting as it suggested that MEF2 plays a role in determining overall cognitive potential in response to variables in the environment,” says Raju.
The researchers then looked at whether MEF2 might 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 has been linked to dementia. When these mice were engineered to overexpress MEF2 at a young age, they did not show the usual cognitive impairments caused by the tau protein later in life. In these mice, neurons overexpressing MEF2 were less excitable.
“Many human studies and mouse model studies on neurodegeneration have shown that the neurons become hyperexcitable in early stages of the disease process,” says Raju. “When we overexpressed MEF2 in a mouse model of neurodegeneration, we saw that it could prevent this overexcitability, which could explain why they outperformed control mice cognitively.”
The results suggest that increasing MEF2 activity may help protect against dementia; However, since MEF2 also affects other cell types and cellular processes, more studies are needed to ensure activation does not have adverse side effects, the researchers say.
The MIT team now hopes to further investigate how MEF2 is activated when exposed to an enriching environment. They also plan to examine some of the effects of the other genes that MEF2 controls, beyond the ion channels they explored in this study. Such studies could help identify additional targets for drug treatments.
“One could potentially envision a more targeted therapy by identifying a subset or class of effectors that is critical for inducing 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.