A multidisciplinary USC research team has identified new compounds that may target a key driver of brain inflammation linked to Alzheimer’s disease. Their research just published in the Nature publication npj Drug Discovery.

The driver is an enzyme called “calcium-dependent phospholipase A2,” or cPLA2. The team discovered its role in brain inflammation by studying people who carry the APOE4 gene — the strongest genetic risk factor for Alzheimer’s disease. While many people who have the APOE4 gene don’t develop the disease, those with elevated levels of cPLA2 generally do.

• RELATED: Read more about the team’s path to discovery.

The problem is that cPLA2 is also essential for normal brain function, so any potential drug molecule would need to inhibit the enzyme’s activity without eliminating it. The molecular candidate would also need to be small enough to cross the blood brain barrier to be effective.

“In this study, we identified compounds that act selectively on cPLA2, with minimal effects on related PLA2 enzymes that are important for normal cellular function,” said senior author Hussein Yassine, director of the Center for Personalized Brain Health at the Keck School of Medicine of USC. “Across cell-based and animal models, cPLA2 activity was reduced at low concentrations, indicating that the compounds are potent in brain-relevant systems.”

Alzheimer’s-linked brain inflammation: Evaluating molecules

Using large-scale computational screening, the team evaluated billions of potential molecules, prioritizing those predicted to be selective, brain-penetrant and active under biologically relevant conditions. Vsevolod “Seva” Katritch of the USC Dornsife College of Letters, Arts and Sciences and the USC Michelson Center for Convergent Bioscience developed the screening methods.

Once the team identified the top candidates, pharmacologist Stan Louie of the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences led the effort to formulate those compounds for administration in animal models and test their levels in the brain.

A cPLA2 inhibitor that reduced pathological cPLA2 activation in human brain cells exposed to Alzheimer’s-related stressors became the prime candidate.

In mouse models, the inhibitor penetrated the blood-brain barrier and modulated neuroinflammatory pathways. The study suggests that inhibiting cPLA2 could be a promising therapeutic approach for neurodegenerative diseases.

“Our goal is to find out whether targeting inflammation can alter Alzheimer’s risk — particularly in APOE4 carriers,” Yassine said. “This next phase focuses not on promises, but on carefully determining whether modulating this pathway is safe, feasible, and ultimately meaningful for human disease.”

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In addition to Yassine, Louie and Katritch, the study was led by co-first authors Anastasiia V. Sadybekov, Marlon Vincent Duro and Shaowei Wang, all of USC. Other authors include Brandon Ebright, Dante Dikeman, Cristelle Hugo, Bilal Ersen Kerman, Qiu-Lan Ma, Antonina L. Nazarova, Arman A. Sadybekov and Isaac Asante, all of USC.

The research was supported with grants from the National Institute on Aging (U01AG094622, RF1AG076124, R01AG055770, R01AG067063, R01AG054434, R21AG056518, and P30AG066530); the National Institute of General Medical Sciences (R01GM147537); Department of Defense (W81XWH2110740), the Alzheimer’s Drug Discovery Foundation (GC-201711–2014197); USC CTSI KL2 (UL1 TR000004); and donations from the Vranos and Tiny Foundations and Lynne Nauss.

Yassine, Katritch and Louie are the founders of PeBRx, which is developing cPLA2 inhibitors. No other authors have any competing interests.

Before married couple Barbara and Glenn Nakahara, both 87, started using hearing aids in 2023, they felt the effects of hearing loss in every aspect of their lives.

“We couldn’t understand what our doctors were saying, and telephone calls were hard,” Barbara Nakahara says. “When you can’t hear something on television or a movie with your family, you really miss a lot.”

The Nakaharas’ experience is typical for those who experience hearing loss and find it increasingly hard to engage with the world around them.

“Hearing loss not only impacts hearing and communication, but also a patient’s relationships, work life and independence,” says Janet Choi, assistant professor of Clinical Otolaryngology – Head and Neck Surgery at the Keck School of Medicine of USC.

Choi is the lead researcher on a new study from the USC Caruso Department of Otolaryngology – Head & Neck Surgery that is the first to link hearing devices, including hearing aids and cochlear implants, to improved social well-being among adults with hearing loss.

“Through the research, I really wanted to understand whether treating hearing loss using hearing aids or via cochlear implantation can have a positive impact on patients’ social lives,” Choi says.

The study, published in JAMA Otolaryngology – Head & Neck Surgery, showed that hearing aids and cochlear implants can improve social engagement and reduce isolation among adults with hearing loss. The research team did a systematic review of 65 studies covering more than 5,000 participants.

Researchers found that hearing devices help people feel more socially connected, more involved in conversations and less lonely. This research follows a January 2024 study by Choi, which showed that adults with hearing loss who use hearing aids have an almost 25% lower risk of mortality. Both studies and other research suggest that treating hearing loss can improve both lifespan and social quality of life.

“Ultimately, our goal as physicians is to have happier, healthier patients,” says Professor John Oghalai, department chair of otolaryngology – head and neck surgery and Leon J. Tiber and David S. Alpert Chair in Medicine at Keck School of Medicine. “This research is really getting to the outcome of helping people be happier, and that’s a direct correlation with our goal of taking care of patients.”

The Nakaharas began to seriously consider hearing devices after Glenn Nakahara’s brother shared that their father had spent his later years socially isolated due to his hearing challenges.

“Glenn’s parents were engaged [with other people] all their lives; people came to visit or they went out to dinner,” Barbara Nakahara says. “To learn that Harry [Glenn’s father] was just sitting there was a really upsetting moment.”

The Nakaharas, already patients at Keck Medicine of USC, then met with audiologist Nicole Greene, who guided them through the process of selecting the best hearing devices for their situation.

Fighting stigma

While the Nakaharas were eager to seek treatment, Choi says that young patients experiencing hearing challenges tend to put up the greatest resistance to using hearing devices.

“There’s a huge social stigma linked to hearing loss and using hearing aids in our society; people think that they make them look old,” Choi says. “As a result, a lot of people are in denial.”

Choi wanted to challenge that stigma because of her personal connection to hearing loss. She was born without a left ear canal due to a congenital condition called aural atresia. A childhood surgery failed to fix the problem completely, so she had to rely almost entirely on her right ear. Although Choi’s pediatrician recommended hearing aids early on, her parents worried that she would be picked on by her classmates.

She didn’t start using hearing aids until a physician who Choi trained with at the University of Minnesota advised that she could be missing crucial words — especially in the operating room, where competing sounds could lead to confusion.

“Hearing aids actually made a huge, positive impact for me, especially in work environments,” Choi says. “I didn’t miss words anymore.”

Relating to patients

Choi’s experience helps her relate to patients with hearing loss — especially those who are newly diagnosed.

“I really like showing my hearing aids to my patients, because they usually don’t even notice that I’m wearing them,” says Choi, who noted that the diversity of options for hearing devices has expanded widely in the last 10 to 20 years. Most patients first think of the bulky, highly visible hearing aids of the past when faced with the reality of hearing loss, but many devices are now smaller, compact and less visible — if patients even want to conceal them.

“I personally advocate for hearing aids as a positive tool to celebrate and embrace,” Choi says. “They can even be a fashion statement at some point.”

Easing access for others

While hearing devices offer a relatively quick source of relief for many patients with hearing loss, finding the best device can be daunting. Choi’s difficulty navigating the hearing loss landscape as a patient — even while working in that field — was an eye-opening experience.

Choi says she had to try different hearing-aid molds and materials before she found the ones that worked for her. “Learning that process myself, I knew we had to do better,” she says. “That’s why I got into hearing-loss research — to understand what treating hearing loss can do and then make it more accessible for everyone.”

Since then, she has authored more than 50 publications in peer-reviewed journals and book chapters and presented at national and international conferences. Her research projects include population-based studies examining the impact of hearing loss and its treatment on health outcomes, as well as the development of artificial intelligence-based solutions to ease access to hearing care.

Reaching across disciplines

Before her fellowship in otology, neurotology and lateral skull base surgery at the University of Minnesota, Choi completed a five-year otolaryngology residency at Keck School of Medicine. She returned to USC as a faculty member and practitioner in 2023, crediting the collaborative nature of her department and USC as an institution as the reason for her return to the university.

“It was the people,” Choi says. “I enjoy working in a very collegial environment, where a lot of collaboration happens not just in my department, but as a whole. USC as an institution, especially for my research, is very multidisciplinary — I have a lot of collaborators in disciplines such as gerontology and neurology.”

“At USC, faculty in different departments want to work together to solve difficult problems and develop innovative ideas,” Oghalai adds. “Our goal is not just to provide medical care, but to advance medical care. And we do that through collaboration and innovation.”

Oghalai hopes Choi’s new research has her desired effect of expanding understanding of the benefits of treating hearing loss.

“My hope is that this research cues people into the idea that [hearing devices] can actually help you accomplish more in your life, and not detract from your life,” he says.

Parsing through the social benefits

Before Choi’s breakthrough finding, many studies already showed that hearing loss is connected to negative social engagement and loneliness. What wasn’t known was whether treating hearing loss with hearing aids or cochlear implantation could have a positive impact on social well-being. For the study, her team reviewed findings from the previous studies and found there was a “really significant, positive impact for both hearing-aid use and cochlear implantation in multiple domains of social outcomes,” Choi says.

Those with cochlear implants reported the biggest improvements in social quality of life, likely because the implants provide greater hearing restoration than hearing aids, especially for people with severe hearing loss. The researchers also found that individuals using hearing devices felt more socially connected and less limited and anxious in social situations.

Like the participants from the study, Choi and the Nakaharas saw their social experiences enriched after treating their hearing loss.

Before using hearing devices, Choi would smile and nod or laugh at a joke without fully understanding when someone spoke to her on her left side.

“That’s something that a lot of people with hearing loss actually do, because it’s cumbersome to have to ask others to repeat themselves constantly,” she said. “You have to pretend in a lot of situations.”

For the Nakaharas, treating their hearing loss meant fully experiencing their granddaughters’ volleyball games for the first time and the promise of better engagement with the girls as they age into college. “At our age you have to enjoy all of this, because we’re not going to be around forever,” Barbara Nakahara says.

“The hearing aids are a very big plus because we can continue to watch them grow happily,” Glenn Nakahara adds.