Researchers in Spain and Switzerland have identified an experimental molecule that could help restore the brain’s natural defenses against Alzheimer’s disease. The compound, known as OLE, appears to be able to “reprogram” the brain’s immune cells, microglia, and regain some of their protective abilities.
The study was led by José Vicente Sánchez Mutto from the Institute of Neuroscience (IN), a joint center of Spain’s National Research Council (CSIC) and Miguel Hernández University of Elche (UMH), and Johannes Gref from the Polytechnic University of Lausanne (EPFL). Their findings were published in the magazine cell death and disease.
According to this study, OLEs help microglia surround and contain beta-amyloid plaques, reducing both their size and their deleterious effects. In animal studies, this treatment also improved performance on memory tests.
How OLE targets Alzheimer’s disease
One of the hallmarks of Alzheimer’s disease is the accumulation of beta-amyloid plaques in the brain. At the same time, the effectiveness of microglia, which normally help remove these toxic deposits, gradually decreases. A reduction in their protective functions can contribute to brain cell damage.
Researchers discovered that OLE, a molecule derived from the PM20D1 gene, can return microglia to a more protective state. After treatment, the cells migrated toward the beta-amyloid plaques, surrounding them and forming a barrier that limited contact between the plaques and nearby neurons. This reduced the toxic effects of plaques on brain tissue.
“One of the most important discoveries was that we identified a molecule that can restore the protective functions of microglia,” explains Sánchez-Mutto. “In Alzheimer’s disease, these cells become progressively impaired. Our results suggest that this process can be reversed and point to new treatments and research avenues to combat Alzheimer’s disease,” added the researchers, who head the Functional Epigenomics of Aging and Alzheimer’s Laboratory at IN CSIC-UMH.
Testing OLE with worms and mice
To evaluate the effectiveness of OLE, researchers used several experimental models.
The first was a genetically engineered nematode (C. elegans) that produces beta-amyloid. These nematodes rapidly develop disease-related lesions, making them a useful method to study virulence. Treatment with OLE reduced the accumulation of protein aggregates and improved animal movement, indicating a protective effect.
The research team then tested the compound in a mouse model of Alzheimer’s disease. Mice were given OLE for three months, after which researchers looked at changes in both memory and the brain. Treated animals performed better on memory tests and had fewer beta-amyloid plaques than untreated mice.
Microglia show the strongest response
To better understand how OLEs work, researchers examined the activity of thousands of individual cells in the brain. Their analysis revealed that microglia were the cells most strongly affected by the treatment.
After exposure to OLEs, microglia activated pathways involved in beta-amyloid clearance and regained the ability to migrate toward and contain plaques.
“Single-cell analysis allowed us to determine that microglia are the cells most responsive to treatment,” says Victoria Pozzi, lead author of the study. “From there, we observed that this compound could help these cells migrate towards beta-amyloid plaques and better limit disease-related damage,” the researchers added.
Additional experiments in cell culture yielded similar results. Microglia treated with OLE more effectively migrated toward beta-amyloid deposits and aided in their removal. In other neuronal cultures exposed to conditions similar to those seen in Alzheimer’s disease, OLE improved cell survival, suggesting that the compound may directly protect neurons.
Possibilities for future Alzheimer’s disease treatment
This discovery is covered by two European patents, including one owned by CSIC. The researchers say this strengthens the translatability of the study and supports future efforts to develop therapeutic applications based on this discovery.
This study was funded by Dementia Research Switzerland – Synapsis Foundation (Switzerland), the Pascual Maragal Researcher Program (PMRP) of the Pascual Maragal Foundation, the Spanish Ministry of Science, Innovation and Universities, the Severo Ochoa Center of Excellence Program of the State Research Agency (AEI), the Prometeo Program of Valenciana Generalitat, the European Regional Development Fund (ERDF), and CSIC. Interdisciplinary thematic platform PTI+ Neuroaging. Additional support was provided by the Swiss National Science Foundation, the Ecole Polytechnique de Lausanne (EPFL), the European Research Council (ERC), the National Research Foundation of Korea (NRF), and the European Social Fund (ESF+).
