Summary: Researchers have identified a new mechanism within neurons that causes memories associated with social interactions to decline with age. Additionally, they were able to reverse memory loss in the mouse models.
Source: University of Maryland
One of the most upsetting aspects of age-related memory decline is not being able to remember the face that accompanies the name of someone you just spoke with a few 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 important new clues.
The study was published on September 8 in aging cell.
Using aging mice, researchers have identified a new mechanism in neurons that causes memories associated with these social interactions to decline with age. What’s more, 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 from typical aging. Memory problems related to aging are distinct from those caused by diseases like Alzheimer’s disease or dementia. Currently, no medication can prevent or reverse cognitive decline due to typical aging.
“If an elderly person attends a cocktail party, they will most likely recognize the names or faces of the other attendees, but they may have difficulty remembering which name matches which face,” said Michy Kelly, Ph. D., head of the study. ., Associate Professor of Anatomy and Neurobiology at UMSOM.
These types of memories that combine multiple pieces of information within a personal interaction, 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 his 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 mice’s “social interactions” with their neighbors by seeing if they’ll be willing to try a new food, based on their memories of encountering that food in another mouse’s breath.
Mice don’t like to eat new foods to avoid getting sick or even dying. When they smell food on the breath of another mouse, the mice establish an association between the smell of the food and the smell of the other mouse’s pheromones, the memory of which serves as a safety signal indicating that any food with that smell is safe to eat in the future.
Dr. Kelly and his colleagues found that although aged mice could recognize food and social smells separately, they were unable to remember the association between the two, similar to cognitive decline in people. elderly.
They also found that PDE11A levels increased with age in humans and mice, particularly in a region of the brain responsible for many types of learning and memory known as the hippocampus.
This extra PDE11A in the hippocampus was not just found where it normally was in young mice; instead, it preferentially accumulated as small filaments in neuron compartments.
The researchers wondered if having too much PDE11A in these filaments was the reason older mice forgot their social associative memories and no longer ate the safe foods they smelled on another’s breath. mouse. To answer this question, they prevented these age-related increases in PDE11A by genetically deleting the PDE11A gene in mice.
Without PDE11A, older mice no longer forgot social associative memory, meaning they ate the safe food smelled on another mouse’s breath. When the researchers reintroduced PDE11A into the hippocampus of these old mice, the mice once again forgot social associative memory and no longer ate the safe foods.
One potential route to developing drugs to prevent this memory loss in people lies in an additional discovery: researchers learned that concentrated PDE11A filaments had an additional chemical modification at one specific location in the enzyme than the other. PDE11 diffused into the neuron had not. have. When they prevented this chemical modification, it reduced the levels of PDE11 and also prevented it from accumulating in the form of filaments.
“PDE11 is involved in more things than memory, including preferences for who you prefer to be around. So if we were to develop a therapy to help with cognitive decline, we wouldn’t want to get rid of it completely or it might cause harm. ‘other negative side effects,’ Dr. Kelly said.
She and her colleagues joke that any drug that eliminates PDE11 would ensure that you remembered your friends and family, but you might not love them anymore.
“So our goal is to find a way to specifically target the wrong form of PDE11A, so as not to interfere with the normal, healthy functioning of the enzyme.”
Dean Mark T. Gladwin, MD, Executive Vice President for Medical Affairs, UM Baltimore, and John Z. and Akiko K. Bowers Professor Emeritus at UMSOM, said, “We are at the tip of the iceberg. When it comes to understanding how the brain ages, it is therefore crucial to have basic research studies like these to help us deepen our understanding and possibly find ways to prevent cognitive decline.
Other study authors include UMSOM students Nicole Gorny, MS, and Siena Petrolle, as well as co-authors from the University of South Carolina.
About this aging and memory research news
Author: Press office
Source: University of Maryland
Contact: Press Office – University of Maryland
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“Age-related conserved increases in hippocampal PDE11A4 cause unexpected proteinopathies and cognitive decline in social associative memories” by Katy Pilarzyk et al. aging cell
Conserved age-related increases in hippocampal PDE11A4 cause unexpected proteinopathies and cognitive decline in social associative memories
In humans, associative memories are more sensitive to age-related cognitive decline (ARCD) than recognition memories. Reduced cAMP/cGMP signaling in the hippocampus may contribute to ARCD.
Here, we found that aging and dementia associated with traumatic brain injury increased expression of the cAMP/cGMP-degrading enzyme phosphodiesterase 11A (PDE11A) in the human hippocampus.
Additionally, age-related increases in hippocampal PDE11A4 mRNA and protein were retained in mice, as was increased vulnerability of associative memories to ARCD recognition. Interestingly, the mouse PDE11A4 protein in the aged ventral hippocampus (VHIPP) accumulated ectopically in the membrane fraction and filamentous structures that we call “phantom axons”.
These age-related expression increases were driven by a reduction in exoribonuclease-mediated degradation of PDE11A mRNA and an increase in PDE11A4-pS117/pS124, the latter also resulting in the punctate accumulation of PDE11A4 . In contrast, PDE11A4-pS162 caused scatter.
Importantly, prevention of age-related increases in PDE11 expression via gene deletion protected ARCD mice from associative short-term and long-term memory (aLTM) in transmission analysis of food preferences, albeit at the expense of recent aLTM.
Moreover, mimicking age-related overexpression of PDE11A4 in CA1 from old KO mice caused age-like alterations in CREB function and remotely, but not non-socially, LTMs. RNA sequencing and phosphoproteomic analyzes of VHIPP identified cGMP-PKG – as opposed to cAMP-PKA – as well as circadian entrainment, glutamatergic/cholinergic synapses, calcium signaling, oxytocin and retrograde endocannabinoid signaling as mechanisms by which PDE11A deletion protects against ARCD.
Together, these data suggest that PDE11A4 proteinopathies acutely impair signaling in the aged brain and contribute to ARCD of social memories.
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