USC-led study finds potential new drug target for Alzheimer’s disease

A team of researchers from the Keck School of Medicine of USC has unlocked the details of a cellular pathway that triggers cellular inflammation and aging and is linked to Alzheimer’s disease, particularly among those who carry the APOE4 genetic risk. They have also found a way to return cells to a healthy state, revealing a new potential approach to treatment. The study, the culmination of a decade of research on a protein known as ATP-binding cassette transporter A1 (ABCA1), was just published in the journal Molecular Neurodegeneration.

Past research found that a shortage of HDL cholesterol (or “good cholesterol) in the brain raises a person’s risk for Alzheimer’s disease. That risk is related to problems with ABCA1, which produces HDL when working properly. But fixing those problems requires understanding the exact biological mechanisms at play—and those details have long eluded researchers, who faced an apparent paradox. In brains affected by Alzheimer’s disease, ABCA1 molecules increased, but their activity decreased.

“This presented a conundrum. There is less HDL in the brain, but the protein that makes it is increased. The obvious question is: Is that protein working as it’s supposed to? We went deep inside cells to figure out what’s happening,” said the study’s corresponding author, Hussein Yassine, MD, a professor of medicine and neurology and director of the Center for Personalized Brain Health at the Keck School of Medicine.

Led by Shaowei Wang, MD, a research associate at the Keck School of Medicine, and funded in part by the National Institutes of Health, the scientists used a range of methods to pinpoint the processes unfolding inside brain cells. They found that in brains of people affected by Alzheimer’s disease or who carried the APOE4 gene putting them at higher risk for the disease, ABCA1 increased, but became trapped in a part of the cell that typically clears waste. That change was linked to a rise in a modified form of cholesterol known as oxysterol. Lowering oxysterol, in both animal models and human stem cells, freed the trapped ABCA1 and restored the pathway to its healthy state.

Lowering oxysterol could be a new way to prevent or treat Alzheimer’s disease in its earliest stages, Yassine said. Past clinical trials that aimed to boost HDL by increasing ABCA1 failed—and this study finally explains why. Without releasing trapped ABCA1, the pathway cannot function as it should.

“This provides new drug targets outside of lowering amyloid or tau, and we need new targets that deal with core issues happening much earlier in the progression of the disease,” Yassine said.

Resetting the ABCA1 pathway

The researchers began by analyzing the ABCA1 pathway, both in mouse models of Alzheimer’s disease and postmortem samples of human brain tissue. They observed ABCA1 getting trapped inside lysosomes, cellular structures responsible for breaking down and clearing waste.

To find out why, they ran a series of discovery experiments, including proteomics and lipidomics, which take a deep dive into proteins and lipids, to look for changes in other molecules that might help explain problems with ABCA1. With support from researchers at USC’s Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, they also measured levels of many forms of cholesterol. Those analyses revealed that an oxidized form of cholesterol, known as oxysterol, was building up inside the cell.

The researchers deduced that elevated oxysterol levels caused ABCA1 to become trapped inside lysosomes. That prevented ABCA1 from producing healthy HDL cholesterol. It also triggered inflammation and cellular senescence, a state common in aging and Alzheimer’s disease in which cells stop replicating.

Those findings suggested that lowering oxysterol levels could help return the ABCA1 pathway to its normal state. In mice, researchers used a drug called cyclodextrin to lower oxysterol, which freed trapped ABCA1 and reduced cellular senescence and neuroinflammation. They repeated a similar study in brain cells grown from human stem cells, again finding that cyclodextrin lowered oxysterol levels and reduced inflammation.

A new treatment target

The study provides a potential explanation for early changes in Alzheimer’s disease that could precede the hallmark buildup of amyloid plaques and tau tangles, the researchers said.

“This fits well with what we know so far about Alzheimer’s disease,” Yassine said. “If we stop and ask why amyloid and tau are accumulating, it’s plausible that is happening because a critical waste recycling system is not working.”

Drugs that lower oxysterols in people at risk for Alzheimer’s disease or in its earliest stages might help prevent the disease from advancing, he said.

Wang, Yassine and their colleagues are also exploring the role of a cellular enzyme known as cytosolic phospholipase A2 (CPLA2). Similar to the ABCA1 pathway, problems with CPLA2 also lead to oxidation that later triggers inflammation in the brain. Inhibiting CPLA2 might offer another way to prevent or treat Alzheimer’s disease.

“Understanding what drives these oxidation processes may be the next frontier for Alzheimer’s researchers,” Yassine said.

About this research

In addition to Yassine and Wang, the study’s other authors are Boyang Li, Jie Li, Zhiheng Cai, Cristelle Hugo, Yi Sun, Helena Chui, Isaac Asante and Bilal Kerman from the Keck School of Medicine of USC, University of Southern California; Dante Dikeman and Stan G. Louie from the Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California; Lu Qian and Julia TCW from the Chobanian & Avedisian School of Medicine, Boston University, Boston, Massachusetts; David Bennett and Zoe Arvanitakis from Rush University Medical Center, Chicago, Illinois; and Alan Remaley from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.

This work was supported by the National Institute on Aging [RF1AG076124, R01AG055770, R01AG067063, R01AG054434, R21AG056518, P30AG066530, R01AG082362, K01AG062683, P30AG10161, P30AG72975 and R01AG15819]; the Alzheimer’s Drug Discovery Foundation [GC-201711-2014197] and donations from the Vranos and Tiny Foundations and Ms. Lynne Nauss.