The study provides some important new clues about age-related memory decline

One of the most disconcerting aspects of age-related memory decline is the inability to remember the face that accompanies the name of a person you just talked to hours earlier. Although researchers don’t understand why this dysfunction occurs, a new study conducted at the University of Maryland School of Medicine (UMSOM) has provided some important new clues. The study was published on September 8 in Senescent cell.

Using aging mice, researchers have identified a new mechanism in neurons that causes memories associated with these social interactions to decline with age. In addition, they were able to reverse this memory loss in the lab.

The researchers report that their findings have identified a specific target in the brain that could one day be used to develop therapies that could prevent or reverse memory loss due to typical aging. Memory problems in aging are different from those caused by diseases such as Alzheimer’s or dementia. There are currently no drugs that can prevent or reverse the cognitive decline associated with typical aging.

If an older person attends a cocktail party afterwards, they will most likely recognize the names or faces of others present, but may struggle to remember which name goes with which face.”

Mitchie Kelly, PhD, study leader, associate professor of anatomy and neurobiology at UMSOM

These types of memories, which connect multiple pieces of information within a personal interaction, so-called social associative memories, require an enzyme known as PDE11A in a part of the brain responsible for memory involving life experiences. Last year, Dr. Kelly published research on PDE11A showing that mice with genetically similar versions of the PDE11 enzyme were more likely to interact than mice with a different type of PDE11A. In this new study, Dr. Kelly and her team sought to determine the role of PDE11A in social associative memory in the aging brain and whether manipulation of this enzyme could be used to prevent this memory loss.

Researchers can study a mouse’s “social interactions” with their neighbors by seeing if they will be willing to try a new food based on their memories of encountering that food on another mouse’s breath. Mice do not like to eat new foods, lest they get sick or even die from them. When they smell food on another mouse’s breath, the mice make a connection between the food odor and the other mouse’s pheromone odor, the memory of which serves as a safety cue that any food with that odor is safe to eat in the future.

Dr. Kelly and her colleagues found that although old mice could recognize food odors and social odors separately, they were unable to remember the association between the two, similar to cognitive decline in older humans.

They also found that PDE11A levels increased with age in both humans and mice, specifically in a brain region responsible for many types of learning and memory, known as the hippocampus. This extra PDE11A in the hippocampus is not simply found where it is normally found in young mice; instead, it preferentially accumulates as small filaments in neuronal compartments.

The researchers wondered if having too much PDE11A in these strands was why the older mice forgot their social associative memories and no longer ate the safe food they smelled on another mouse’s breath. To answer this question, they prevented these age-related increases in PDE11A by genetically deleting the PDE11A gene in mice. Without PDE11A, the older mice no longer forgot the social associative memory, meaning they ate a safe food smelling of another mouse’s breath. When the researchers added PDE11A back into the hippocampus of these old mice, the mice again forgot the social associative memory and no longer ate the safe food.

One potential path toward developing drugs to prevent this memory loss in humans lies in an additional discovery: The researchers learned that the concentrated strands of PDE11A have an additional chemical modification at a specific site on the enzyme that the other PDE11 scattered throughout the neuron does not. they have When they prevented this chemical modification, it reduced PDE11 levels and also prevented it from accumulating as filaments.

“PDE11 is involved in more than just memory, including preferences for who you prefer to be with. So if we were to develop a therapy to help with cognitive decline, we wouldn’t want to get rid of it entirely or it could cause other negative side effects,” Dr. Kelly said. She and her colleagues joke that any drug that eliminates PDE11 will ensure that you remember your friends and family, but you may no longer like them. “Thus, our goal is to find a way to specifically target the bad form of PDE11A so as not to interfere with the enzyme’s normal, healthy function.”

Dean Mark T. Gladwin, MD, executive vice president for medical affairs, UM Baltimore, and John Z. and Akiko K. Bowers, UMSOM Distinguished Professor, said, “We are at the tip of the iceberg when it comes to understanding how the brain ages, so it’s critical that we have basic research like this to help us improve our understanding and ultimately find ways to prevent cognitive decline.”

Additional study authors include UMSOM graduate students Nicole Gorney, MS, and Siena Petrolle, as well as co-authors from the University of South Carolina.