Restoring Cognitive Function for Alzheimer’s Disease

While most research on Alzheimer’s has focused on early diagnosis and treatment, the new study is focusing on finding novel ways to restore cognitive function and will utilize studies in mouse models carrying gene mutations for familial Alzheimer’s (where more than one family member has the disease) and in human stem cell-derived neurons from Alzheimer’s patients.

The work involving preclinical research to unravel genetic and epigenetic factors that cause Alzheimer’s is funded by a five-year, $2 million grant from the National Institutes of Health’s National Institute on Aging. Zhen Yan, PhD, professor of physiology and biophysics, is principal investigator.

Epigenetic factors can change gene expression without altering the underlying DNA sequence — which in turn affects how cells read the genes. Such changes may profoundly impact human health.

“We hypothesize that Alzheimer’s is produced by a combination of genetic risk factors and environmental factors, such as aging, that induce the dysregulation of specific epigenetic processes that lead to impaired cognition,” Yan says.

The research will explore how epigenetic changes that accompany Alzheimer’s disease also might help identify a much sought-after biomarker for the disease, which could allow for novel treatment.

Numerous clinical trials in recent years have focused on reducing amyloid beta plaque in the brain. So far, such efforts haven’t yet translated into improving cognitive function, Yan says.

“Our research, by contrast, will target synaptic function, which is at the root of cognitive function,” she explains. “Our hypothesis is that this approach will have a more fundamental effect.”

Yan and her colleagues will investigate aberrant histone methylation, an epigenetic process that affects the expression of genes encoding key proteins that allow for signals to be transmitted between neurons.

When this process is dysregulated in Alzheimer’s disease, neuronal signaling doesn’t function properly, leading to cognitive impairment.

Even though Alzheimer’s patients can often easily remember something that happened 20 years ago, the later stages of the disease are characterized by a growing inability to recall recently learned information.

That kind of short-term working memory, Yan explains, is dependent on excitatory transmission in the frontal cortex, mediated by glutamate receptors.

“At the later stages of the disease, we know that there is a loss of glutamate receptors that are crucial for learning and memory,” she says. “When these receptors lose the ability to communicate, there is a loss of cognition.”

“Our research will try to restore gene expression in these glutamate receptors using epigenetic tools, with the ultimate goal of restoring cognitive function.”

Jian Feng, PhD, professor of physiology and biophysics, is a co-investigator on the grant titled “A Novel Epigenetic Mechanism for Alzheimer’s Disease.”