Cellular reprogramming helps overcome progressive Alzheimer’s disease

A team led by researcher José Vicente Sánchez Mut at the Institute of Neurosciences (IN), a joint center of the Spanish National Research Council (CSIC) and the Miguel Hernández University of Elche (UMH), together with researcher Johannes Gräff at the École Polytechnique Fédérale de laus. “reprogramming” the cells of the brain’s immune system to restore some of their protective function against Alzheimer’s disease.

The study, published in the journal Cell death and diseaseshows that the compound, called OLE, helps microglia encapsulate and contain beta-amyloid plaques, reducing their size and toxicity. In animal models, the treatment also improved cognitive performance on memory tests.

Alzheimer’s disease is characterized, among other factors, by the accumulation of beta-amyloid plaques and the progressive deterioration of microglia, the immune cells responsible for removing these toxic deposits from the brain. As the disease progresses, these cells lose some of their protective capacity and contribute to neuronal damage.

In this study, the researchers found that OLE, a molecule derived from the PM20D1 gene, helps restore microglia to a more protective state: the cells move towards the plaques and surround them, forming a kind of barrier around the deposits that limits their interaction with neurons and reduces their toxic effect on brain tissue.

One of the most important findings is that we have identified a molecule capable of restoring the protective function of microglia. In Alzheimer’s disease, these cells are progressively weakened. Our results suggest that this process can be reversed, pointing to new therapeutic and research avenues to address the disease.”

José Vicente Sánchez Mut, Researcher, Institute of Neurosciences

He also leads the Functional Epi-Genomics of Aging and Alzheimer’s Disease laboratory at IN CSIC-UMH.

Effects of OLE in experimental models

To study the effects of OLE, the team combined different experimental models. First, they used genetically modified worms (C. elegans) was engineered to produce beta-amyloid, allowing researchers to rapidly assess its toxicity. In this model, OLE treatment reduced the accumulation of protein aggregates and improved worm motility, suggesting a protective effect against disease-related damage.

The team then administered the compound for three months to mouse models of Alzheimer’s disease to analyze its effects on the brain and memory. After treatment, the animals showed improved performance on memory tests and a reduction in beta-amyloid plaques associated with the disease.

To understand how OLE works in the brain, the team analyzed the activity of thousands of individual cells. The results showed that microglia were the cell type most affected by the treatment. After administration of the compound, these cells activated mechanisms involved in the clearance of beta-amyloid and regained their ability to move towards and enclose the plaques.

“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 move towards the beta-amyloid plaques and better contain the damage associated with the disease,” adds the researcher.

In addition, the team confirmed in cell cultures that microglia treated with OLE showed an increased ability to move towards β-amyloid deposits and promote their clearance. Similarly, in neuronal cultures exposed to stress conditions similar to those seen in Alzheimer’s disease, the treatment increased cell survival, suggesting that it also exerts a direct protective effect on neurons.

The findings of the study are protected by two European patents, one of which belongs to CSIC. According to the authors, this advance enhances the translational potential of the research and its possible future development in the therapeutic field.