Study Finds Key Enzyme Linked to Memory Problems in Old Age, Based on Research in Mice

A study published in the journal Frontiers in Molecular Neuroscience states that everyone has moments of forgetfulness from time to time, especially as we get older. But older adults don’t just have difficulty remembering new information. They also have a harder time modifying those memories when new details emerge. Yet, little is known about the mechanisms behind memory updating and how those mechanisms go awry with age.

A team of researchers from Penn State has identified an enzyme that contributes to age-related impairments in memory updating. When blocked, older mice were better able to incorporate new information and performed similarly to their younger counterparts. The researchers said that the findings may lead to the development of potential therapeutic targets for improving cognitive flexibility in old age.

When a memory forms, the brain rewires itself to keep that memory in place through a process called consolidation. Cells express proteins at the synapse, the gap between neurons that allows communication between nerve cells, linking together the cells activated when the memory formed. When the memory is recalled, those cells then fire together at the same time

In this study, the research team wanted to understand why it’s harder to update memories with normal aging. To test this, they blocked histone deacetylase 3 (HDAC3), an enzyme that regulates gene transcription, the process of copying information from a DNA segment into RNA that will ultimately make a functional protein. HDAC3 has been shown to negatively affect memory formation and gene expression during consolidation but the researchers said its role in memory reconsolidation wasn’t previously studied.

HDAC3 typically tightens up the chromatin, a complex of DNA and proteins, and makes it hard for transcription to happen. If this enzymatic activity is blocked from happening, it may help maintain a more open chromatin state and improve gene expression. When HDAC3 was blocked during the memory reconsolidation phase, it prevented the typical age-related deficits in memory updating. Older mice performed as well as their younger counterparts during a memory update task.

The team used a methodology called the objects in updated locations paradigm, which Kwapis developed specifically to test memory updating. It includes three phases: a training session where mice learn two locations of identical objects; an update session where one of the objects is moved to a new location; and a test session where the objects are placed in four separate locations — the original two training locations, the updated location and a completely novel location.

The study found that alterations in this enzyme's activity could contribute to cognitive decline in older age. The research highlights the potential of targeting this enzyme as a therapeutic strategy to mitigate memory loss and other cognitive impairments associated with ageing. However, further studies in humans are needed to confirm these findings and develop effective treatments.

References: Alaghband, Y., Kwapis, J. L., López, A. J., White, A. O., Aimiuwu, O. V., Al-Kachak, A., et al. (2017). Distinct roles for the deacetylase domain of HDAC3 in the hippocampus and medial prefrontal cortex in the formation and extinction of memory. Neurobiol. Learn. Mem. 145, 94–104. doi: 10.1016/j.nlm.2017.09.001