Blocking an enzyme improves age-related memory problems

Researchers have identified an enzyme that is key to updating existing memories with new information, a process that naturally declines with age. Blocking the enzyme improved memory decline, opening the door to developing treatments for age-related memory problems.

There has been a lot of research into how memories are formed, but less into how existing memories are updated with new information – even though scientists know that our ability to modify or update existing memories declines with age and may contribute to age-related cognitive decline. But now, new research has identified a key molecular mechanism behind memory updating.

Researchers at Pennsylvania State University (Penn State) wanted to understand why normal aging makes it harder to update memories. In search of an answer, they found an enzyme that, when blocked in old mice, prevented the age-related memory deficits typically seen.

“It’s important to understand what happens at the molecular level during a memory update because, as humans, most of our memories are updates,” said Janine Kwapis, an assistant professor of biology at Penn State and senior author on the study. “But no one has really investigated whether the mechanisms behind memory formation and updating are identical or whether they are unique to memory updating. This is a step forward in finding out.”

Consolidation is the process by which a newly formed short-term memory is transformed into a more stable long-term memory. That stabilization depends on gene-controlled protein synthesis at the synapse, the space between neurons that allows them to pass signals to each other. As new experiences and memories are acquired, the brain essentially reorganizes itself to create more of these synaptic connections. Eventually, two connected neurons become sensitized to each other, so that when a memory is recalled, they fire simultaneously.

“When new information is presented, that existing memory has to be pulled out of storage and weakened so that it is ready to receive new information,” Kwapis said. “Once the new information is learned and those new neurons are recruited, the updated memory is solidified and stored again.”

This process is called reconsolidation, and it becomes less effective with age. So the researchers looked at whether enhancing gene expression during reconsolidation would also improve memory updating ability. They knew that histone deacetylase 3 (HDAC3), an enzyme that regulates the copying of information from a segment of DNA into RNA that is eventually converted into a protein, has been shown to negatively affect memory formation and gene expression during consolidation, so they focused on it.

“HDAC3 typically tightens chromatin, a complex of DNA and proteins, and hinders transcription,” said Chad Smies, a Penn State biology doctoral student and senior author on the paper. “If we block this enzymatic activity, it may help maintain a more open state of chromatin and enhance gene expression.”

Older male mice (18–20 months old) were given the object-in-an-updated-location task. After becoming familiar with an environment, the animals were exposed to two identical objects placed at specific locations. Twenty-four hours later, the environment was updated: one of the identical objects was moved to a new location. Immediately after the update session, the mice were given either a placebo or a drug to block HDAC3. The mice’s memory for the objects was then tested. Four identical objects were placed at specific locations within the environment: two at the original locations, one at the updated location, and a fourth at a completely new location.

“Mice like novelty, so if they have a good memory for the training session or the update session, they will explore the novel object location more,” Smies said. “But if they have a poor memory, they tend to explore the previously learned locations as much as the new location.”

The researchers found that blocking HDAC3 immediately after the refresher session reduced age-related memory declines without affecting the original memory. Older mice performed just as well as younger mice during the memory test.

The research team hopes that identifying molecular mechanisms that affect memory, such as HDAC3, will pave the way for the development of therapeutic targets to improve age-related reduced cognitive flexibility.

“If these mechanisms improve memory in normal aging, they could potentially help in diseases such as Alzheimer’s and dementia as well,” Kwapis said.

The study was published in the journal Frontiers in molecular neuroscience.

Source: Penn State