Researchers from Spain and Switzerland have identified an experimental molecule that may help restore the brain’s natural defenses against Alzheimer’s disease. The compound, known as OLE, appears to “reprogram” microglia, the brain’s immune cells, allowing them to regain some of their protective abilities.
The research was led by José Vicente Sánchez Mut from the Institute of Neurosciences (IN), a joint center of the Higher Council for Scientific Research (CSIC) and the Miguel Hernández University of Elche (UMH), together with Johannes Gräff from the École Polytechnique Fédérale de Lausanne (EPFL). Their findings were published in the journal Cell death and disease.
According to the study, OLE helps microglia surround and contain beta-amyloid plaques, reducing both their size and harmful effects. In animal studies, the treatment also led to better performance on memory tests.
How OLE attacks Alzheimer’s disease
One of the hallmarks of Alzheimer’s disease is the buildup of beta-amyloid plaques in the brain. At the same time, microglia, which normally help remove these toxic deposits, gradually become less effective. As their protective functions decline, they can contribute to brain cell damage.
The researchers found that OLE, a molecule derived from the PM20D1 gene, can return microglia to a more protective state. After treatment, the cells moved toward and surrounded the beta-amyloid plaques, creating a barrier that limited contact between the plaques and nearby neurons. This reduced the toxic impact of the plaques on brain tissue.
“One of the most significant findings is that we have identified a molecule capable of restoring the protective function of microglia,” explains Sánchez Mut. “In Alzheimer’s disease, these cells deteriorate progressively. Our results suggest that this process can be reversed, which points to new therapeutic and research avenues to counteract the disease,” adds the researcher, who directs the Functional Epigenomics of Aging and Alzheimer’s Disease laboratory at the IN CSIC-UMH.
OLE test in worms and mice
To evaluate the effects of OLE, the researchers used several experimental models.
The first involved genetically modified worms (C. elegans) that produce beta-amyloid. Because these worms quickly develop disease-related damage, they provide a useful way to study toxicity. OLE treatment reduced the accumulation of protein aggregates and improved the movement of animals, indicating a protective effect.
The team then tested the compound in mouse models of Alzheimer’s disease. The mice received OLE for three months, after which the researchers examined both memory and brain changes. Treated animals performed better on memory tests and showed fewer beta-amyloid plaques than untreated mice.
Microglia show the strongest response
To better understand how OLE works, researchers examined the activity of thousands of individual cells in the brain. Their analysis revealed that microglia were the cells most affected by the treatment.
Following exposure to OLE, microglia activated pathways involved in removing beta-amyloid and regained their ability to move toward and contain plaques.
“The single-cell analysis allowed us to determine that microglia were the cells that responded most strongly to the treatment,” says Victoria Pozzi, first author of the study. “From there, we observed that the compound helped these cells advance towards the beta-amyloid plaques and better contain the damage associated with the disease,” adds the researcher.
Additional experiments in cell cultures produced similar results. OLE-treated microglia were more effective at moving toward beta-amyloid deposits and helping to clear them. In separate neuronal cultures exposed to conditions similar to those seen in Alzheimer’s disease, OLE improved cell survival, suggesting that the compound may also directly protect neurons.
Potential for future Alzheimer’s therapies
The findings are covered by two European patents, including one owned by the CSIC. The researchers say this strengthens the translational potential of the work and supports future efforts to develop therapeutic applications based on the discovery.
The study received funding from Dementia Research Switzerland — Synapsis Foundation (Switzerland), the Pasqual Maragall Researchers Program (PMRP) of the Pasqual Maragall Foundation, the Ministry of Science, Innovation and Universities of Spain, the Severo Ochoa Centers of Excellence program of the State Research Agency (AEI), the Prometheus program of the Generalitat Valenciana, the European Regional Development Fund (ERDF) and the Interdisciplinary Thematic Platform of the CSIC PTI+ NEURO-AGING. Additional support came from the Swiss National Science Foundation, the École Polytechnique Fédérale de Lausanne (EPFL), the European Research Council (ERC), the National Research Foundation of Korea (NRF), and the European Social Fund (ESF+).