Yun Lei, PhD, assistant professor in the Department of Neuroscience and Regenerative Medicine at the Medical College of Georgia at Augusta University, received a nearly $2.8 million R01 grant from the National Institutes of Health to study Alzheimer’s disease, according to a Mar. 19 announcement. Lei also recently had a research paper accepted for publication by the journal Molecular Psychiatry.
The new funding and publication highlight ongoing efforts to better understand why certain neurons are more vulnerable in Alzheimer’s disease and how this knowledge could lead to improved treatments.
Lei’s five-year NIH-funded project, which began in January, focuses on epigenetic mechanisms that may make specific neurons in the entorhinal cortex more susceptible to damage during early stages of Alzheimer’s. The entorhinal cortex is important because it sends information to the hippocampus, which is central to memory formation. “There are all different kinds of neurons in the brain, but not all of them are affected by Alzheimer’s disease,” Lei said. “So we are focusing on the most vulnerable brain region, and then one group of neurons in that region that is particularly vulnerable to the development of the disease.”
Lei explained that gene expression can change with age or environmental factors without altering DNA itself—a process called epigenetic regulation. “It’s not changing your genes or your DNA, but it can change how certain genes are turned on or off – we call that epigenetic regulation. When this process doesn’t work properly, it can speed up aging and increase the risk of diseases like Alzheimer’s,” she said.
Her research links progression of Alzheimer’s disease to an enzyme called EZH2, which modifies proteins associated with DNA and affects gene accessibility. Early data shows EZH2 is dysregulated in neurons from mouse models with Alzheimer’s. The team will investigate whether EZH2 helps maintain neuronal function during aging and protects against amyloid beta plaques and tau tangles—two hallmarks of Alzheimer’s.
“Alzheimer’s disease is a devastating neurodegenerative disorder that causes memory loss. It is very complex, and we still do not fully understand the mechanisms behind its development,” Lei said.
In addition to her grant work, Lei authored a paper titled “Neuronal HDAC9: A key regulator of cognitive and synaptic aging, rescuing Alzheimer’s disease-related phenotypes.” This study examines another enzyme—HDAC9—and its role in cognitive decline related to aging and Alzheimer’s progression. Collaborating with Xin-Yun Lu, MD, PhD, professor and chair at MCG’s Department of Neuroscience and Regenerative Medicine, they found HDAC9 levels decrease with age in both human and mouse brains.
“Many previous studies have focused on Class I HDACs, but we’re looking at Class II HDAC9 in our study to understand its specific role in aging and Alzheimer’s disease,” Lei said.
Their experiments showed young mice lacking HDAC9 had impaired cognition while increasing HDAC9 helped preserve learning abilities as mice aged. Overexpression also reduced cognitive deficits and amyloid plaques in mouse models for Alzheimer’s.
“When we first observed this, it was surprising, as it contradicts the prevailing idea in the field that HDAC inhibition is beneficial in Alzheimer’s disease,” Lu said.
Lu added: “Dr. Lei’s work brings competitive federal funding to Augusta University, and her discoveries may lead to new strategies for preventing or treating this devastating disease… Her laboratory also provides training opportunities for graduate students and postdoctoral fellows.”
