MCG scientists investigate arthritis drug’s impact on Alzheimer’s disease

According to the Alzheimer’s Association, more than 7 million Americans are living with Alzheimer’s disease, and one in nine of those people is 65 or older. Although that number is expected to grow, researchers at the Medical College of Georgia at Augusta University are making progress on studies that could turn into life-saving treatments.

Qin Wang, MD, PhD, professor in the Department of Neuroscience and Regenerative Medicine at MCG and Georgia Research Alliance Eminent Scholar in neuropharmacology, recently published a study titled “The PKCι‑β‑arrestin2 axis disrupts SORLA retrograde trafficking, driving its degradation and amyloid pathology in Alzheimer’s disease,” in Molecular Degeneration, a leading journal in neurodegeneration.

In the study, Wang and her team explored how certain proteins and enzymes interact in the brains of Alzheimer’s patients. Key players include the SORL1 gene, the PKCι enzyme and proteins SORLA, β‑arrestin2 and amyloid.

SORL1 encodes SORLA, which helps regulate amyloid. Amyloid can form plaque in the brain, contributing to Alzheimer’s. People with the disease often have lower SORLA levels, which amplifies plaque production. 

“The goal is to increase SORLA levels in patients with AD. If we can boost it up, that would be great,” Wang said. “But if you want to know how to boost it up, you have to know how it is degraded, so that’s what our work is about – we’re trying to understand how its stability is regulated.”

Wang’s research team found that PKCι can add a phosphate group to SORLA, which helps SORLA interact with β‑arrestin2. The PKCι‑β‑arrestin2 axis leads to SORLA degradation, reducing its levels and allowing amyloid plaques to grow unchecked, thereby worsening the disease condition.

They discovered this by using biochemical methods and a mass spectrometer managed by Wenbo Zhi, PhD, at the Proteomics and Mass Spectrometry core lab at AU.

“We conducted biochemical studies and found that SORLA can be phosphorylated. We identified the phosphorylation site and the interacting enzymes,” Wang explained. “Using the mass spectrometer with PKCι, we saw increased phosphorylation of SORLA at certain sites. Preventing that could stop SORLA degradation.”

That’s where a rheumatoid arthritis drug called auranofin comes into play.

“While it is an arthritis drug, it can also inhibit the PKCι enzyme,” Wang explained. 

The team conducted tests using Alzheimer’s mouse models and human iPS cells developed into neurons. For the mouse models, they treated the mice with auranofin for eight weeks, resulting in decreased amyloid levels, reduced neuroinflammation and improved cognitive function. Similar results were seen in human cells with increased SORLA levels and decreased amyloid levels.

“A good thing about this is, because this is an FDA-approved drug, it’s ready to be tested in Alzheimer’s patients,” Wang said. “People often worry about drug safety because of long-term use in chronic diseases like Alzheimer’s, but, in this case, existing safety data for chronic use gives a good starting point for testing in Alzheimer’s patients.

“I hope a drug company can pick that up for a trial with Alzheimer’s patients because we are trying to translate our bench work all the way to the bedside for treatment,” she continued.

The study wraps up a five-year National Institute on Aging grant, a collaborative effort between Wang’s lab and the Kai Jiao, MD, PhD, lab in AU’s Center of Biotechnology and Genomic Medicine. Wang’s team is also working on other grant-funded Alzheimer’s-related projects and hopes to continue making advancements toward finding a cure for this debilitating disease.

“All of our projects share the goal of finding a better treatment,” Wang said. “Related to this project in particular, we want to know how the SORLA protein works in different types of brain cells, given the brain’s complexity. Then we can determine how to specifically target that protein to develop more effective therapies.”