A team of researchers from the Keck School of Medicine at the University of Southern California (USC) has uncovered crucial details about a cellular pathway linked to Alzheimer’s disease, particularly in individuals with the APOE4 genetic risk. Their findings reveal a potential new approach to treatment, focusing on returning cells to a healthy state. The study, published in Molecular Neurodegeneration, marks a significant milestone in a decade-long investigation into the ATP-binding cassette transporter A1 (ABCA1) protein.
Earlier studies have shown that a shortage of HDL cholesterol—often referred to as “good cholesterol”—in the brain increases the risk of Alzheimer’s. ABCA1, which is responsible for producing HDL, plays a key role in this process. However, researchers have struggled to understand the specific biological mechanisms behind ABCA1’s malfunction in Alzheimer’s disease, particularly when ABCA1 levels are elevated, but its activity is diminished.
“This presented a conundrum,” explained Dr. Hussein Yassine, corresponding author of the study and director of the Center for Personalized Brain Health at Keck School of Medicine. “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.”
Led by Shaowei Wang, a research associate at the Keck School of Medicine, and funded in part by the National Institutes of Health, the research team used advanced methods to explore the cellular processes inside brain cells. They discovered that in individuals affected by Alzheimer’s or carrying the APOE4 gene, ABCA1 accumulates but becomes trapped in a cellular compartment responsible for waste clearance. This accumulation coincided with elevated levels of oxysterols, a modified form of cholesterol. Lowering oxysterol levels, both in animal models and human stem cells, freed the trapped ABCA1, restoring its function.
“This finding suggests that lowering oxysterol could offer a new approach to preventing or treating Alzheimer’s disease, particularly in its earliest stages,” said Dr. Yassine. “Previous clinical trials aimed at boosting HDL by increasing ABCA1 were unsuccessful—and this study finally explains why. Without releasing trapped ABCA1, the pathway cannot function properly.”
The research offers a fresh perspective on drug targets, providing potential alternatives to current therapies that focus primarily on amyloid plaques and tau tangles, hallmark features of Alzheimer’s disease. “We need new targets that address core issues occurring much earlier in the disease’s progression,” Dr. Yassine said.
Restoring the ABCA1 Pathway
The study focused on the ABCA1 pathway in mouse models and human postmortem brain samples. The researchers found that ABCA1 was being trapped inside lysosomes, cellular structures responsible for waste breakdown. To understand why, they employed proteomics and lipidomics—methods that examine proteins and lipids at a detailed level—to identify changes in other molecules contributing to the dysfunction of ABCA1. They also measured various forms of cholesterol and identified the accumulation of oxysterols inside the cells.
The researchers concluded that elevated oxysterol levels caused ABCA1 to become trapped in the lysosomes, preventing it from producing HDL cholesterol. This malfunction triggered inflammation and cellular senescence, a state commonly observed in aging and Alzheimer’s disease, in which cells stop replicating.
By using a drug called cyclodextrin to lower oxysterol levels in mice, the researchers were able to free the trapped ABCA1, reduce cellular senescence, and decrease neuroinflammation. Similar results were obtained in human stem cell-based brain models.
A New Potential Treatment Target
The findings also provide a possible explanation for early Alzheimer’s changes that may precede the development of amyloid plaques and tau tangles, the researchers noted. “This fits well with what we know so far about Alzheimer’s disease,” Dr. Yassine said. “If we stop and ask why amyloid and tau are accumulating, it’s plausible that this happens because a critical waste recycling system is not working.”
The team is now exploring the role of another enzyme, cytosolic phospholipase A2 (CPLA2), which also contributes to oxidation and inflammation in the brain. Inhibiting CPLA2 could provide another potential avenue for preventing or treating Alzheimer’s disease.
“Understanding the mechanisms that drive these oxidation processes may be the next frontier for Alzheimer’s research,” Dr. Yassine concluded.
Research Team and Funding
In addition to Dr. Yassine and Dr. Wang, the study’s authors include Boyang Li, Jie Li, Zhiheng Cai, Cristelle Hugo, Yi Sun, Helena Chui, Isaac Asante, and Bilal Kerman from the Keck School of Medicine at USC; Dante Dikeman and Stan G. Louie from the Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences at USC; Lu Qian and Julia TCW from the Chobanian & Avedisian School of Medicine, Boston University; David Bennett and Zoe Arvanitakis from Rush University Medical Center; and Alan Remaley from the National Heart, Lung, and Blood Institute.
This groundbreaking research opens the door to new treatment strategies that could address Alzheimer’s disease at an earlier stage, potentially altering the trajectory of the disease for millions of people at risk.
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