Alzheimer's disease currently affects 5.8 million Americans, and 13.8 million people over the age of 65 are expected to develop the disease by 2030. Cognitive decline is a consistent factor in typical aging and Alzheimer's disease, according to Penn State Associate Professor of Biology Janine Kwapis, yet the cellular and molecular mechanisms underlying this process remain an unsolved challenge. With a new two-year, $432,575 award from the National Institutes of Health's (NIH) National Institute of Aging (NIA), Kwapis is working to solve the challenge.
The grant is funded via NIH's R21 award mechanism, which is meant to launch new areas of inquiry and assist early-stage innovation into research that will enhance human health. Kwapis, director of the Center for Molecular Investigation of Neurological Disorders and member of the Penn State Neuroscience Institute, studies the molecular and epigenetic mechanisms that support long-term memory formation, storage and updating in order to better understand how these mechanisms are dysregulated as humans get older and lead to age-related memory impairments.
"Aging is the single most important risk factor for Alzheimer's disease, and identifying the biology underlying cognitive decline is an important step toward improving cognition in both old age and in Alzheimer's," said Kwapis, who is also affiliated with the Huck Institutes of the Life Sciences.
Kwapis' new grant aims to address the decline in memory updating, the ability to modify existing memories with new information. In her preliminary research in mice, she investigated the mechanisms that support updating in the hippocampus, a brain region that is especially vulnerable to the effects of aging in both rodents and humans.
She found that the memory impairments may stem from disrupted collocation or "overlap" between the neuronal ensembles, groups of neurons displaying recurring patterns of coordinated activity, supporting the original and updated memories.
"Historically, most of the basic research on memory has focused on brand new memory formation," Kwapis said. "I'd argue, however, that most of human memories are updates - tweaks and modifications to things we have already learned - yet we understand far less about how existing memories are changed."
The researchers use an approach called Objects in Updated Locations (OUL) to test memory in mice. The lab begins with a simple memory task - learning the locations of two objects in a familiar environment. Then, the researchers update the memory by moving one object to a new location and test the memory, allowing them to determine if the original memory is intact and if a memory update was learned.
"When young mice update a memory, they reactivate and modify these memory cells, incorporating the new information into that existing memory trace," Kwapis said. "We think that old mice reactivate the wrong cells, making it difficult to incorporate the new information into the existing memory."
In earlier research, Kwapis found evidence that suggests that the repressive histone deacetylase 3 (HDAC3) - a protein that inhibits some gene expression - might contribute to age-related updating impairments, and blocking HDAC3 may improve memory updating in older mice.
With the new funding, Kwapis and her team plan to manipulate HDAC3 activity in a mouse model to investigate how inhibiting neurons in original memory ensembles can overcome age-related and HDAC3-driven deficits.
Kwapis said her ultimate goal during this research process is to uncover new potential therapeutic targets that could help improve memory flexibility in older adults.
"I have been fascinated by memory updating since I was a graduate student, and this award gives us the funding to finally tackle some of the questions that I have been mulling over for the past decade," Kwapis said. "This award will allow us to solve the mystery of why memory updating is impaired in old age, and why memories get rigid and inflexible. We are really grateful for this support from NIA."
This work is supported by the National Institutes of Health's National Institute of Aging under award number R21AG090642. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.
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