Joon Kong - professor of chemical and biomolecular engineering
The gene most strongly associated with Alzheimer’s disease, APOE4, has been found to increase seizure activity by reducing levels of ion pumps and energy-producing enzymes in neurons, according to a new study by researchers at the University of Illinois Urbana-Champaign. This discovery opens the door to potential treatments, as researchers demonstrated that a blood pressure medication could stimulate the energy-making pathway and reduce seizures in mouse models of Alzheimer’s.
“Seizures are very prevalent symptoms of Alzheimer’s disease patients. 10-22% experience unprovoked seizures, while up to 50% show subclinical epileptic activity, or hyperactivity in the brain,” said study leader Hee Jung Chung, a professor of molecular and integrative physiology at the University of Illinois. “The APOE4 gene increases the risk of developing Alzheimer’s disease twelvefold compared to the normal APOE3 gene—and, interestingly, it also has been linked with seizures.”
Understanding the Link Between APOE4 and Seizures
Chung’s research team aimed to determine when brain hyperactivity occurs in mice carrying the human APOE4 gene. This was crucial, as most studies focus on a single age group. Illinois postdoctoral researcher Tanveer Singh and Emma Bridgeman, a co-first author of the paper, found that mice began experiencing more seizures and seizure-induced deaths between 5.5 and 7 months of age, which is roughly equivalent to a human in their 30s. Younger mice appeared unaffected.
The study also examined seizure activity in mice with APOE4 and tau protein tangles, a hallmark of Alzheimer’s disease. Results showed that female mice with both APOE4 and tau tangles had more severe seizures, although the presence of tau tangles did not affect male mice.
“There’s a sex difference in Alzheimer’s disease-related dementia and seizure prevalence in humans too, with females more likely to develop Alzheimer’s disease,” Chung noted. “We don’t know why; however, our data suggests that the difference in seizure susceptibility may play a role.”
Exploring Treatment Pathways
The researchers investigated how APOE4 increases brain hyperactivity and seizures by examining genes and proteins in the hippocampus, the primary brain region affected by Alzheimer’s. They discovered reduced levels of the sodium and potassium ion pump that regulates neuron activity.
“If we decrease this pump activity, it leads to increased firing of action potentials of neurons, indicative of neuronal network hyperactivity that underlies seizures,” Chung explained.
Given the pump’s ubiquitous presence in all brain cell types, it is not a viable treatment target. Instead, the researchers focused on increasing ATP, the cellular energy driving the pump. They found that both ATP and the enzymes producing it during metabolism were in low supply in the hippocampi of APOE4 mice compared to those with the APOE3 gene.
“Our study revealed a clear link between reduced ATP levels, ion pump dysfunction, and seizure susceptibility,” Singh said.
Potential Treatment with Terazosin
To increase ATP levels, the team treated mice with terazosin, a blood pressure medication recently found to enhance ATP-making enzymes. Terazosin treatment increased ATP levels in the hippocampus and decreased seizure activity in APOE4 mice and female mice with both APOE4 and tau tangles.
The study, published in the journal Neurobiology of Disease, suggests that terazosin could be repurposed to reduce seizures or brain hyperactivity in Alzheimer’s patients. The next phase of research will explore whether reducing seizures can mitigate memory deficits or slow dementia progression.
Additionally, researchers combined terazosin with an inhibitor to ensure glucose in neurons is converted to ATP rather than lactose, further enhancing ATP levels and suppressing seizure activity. This indicates that methods to increase ATP in the hippocampus are worth exploring for controlling seizure activity in those with the APOE4 gene.
“We know that exercise improves cognition and increases ATP production. However, most aged populations, and especially Alzheimer’s disease patients, do not get enough exercise. We are now investigating if terazosin treatment alone or in combination with voluntary exercise mitigates memory loss and brain pathology in APOE4 mice by blocking ATP reduction and seizures,” Chung said.
This research was supported by the U.S. National Institutes of Health and the Alzheimer’s Association. Chemical and biomolecular engineering professor Hyunjoon Kong and physics professor Paul Selvin were co-authors of the work.
