A common cholesterol-lowering drug, bezafibrate, could prove useful in treating frontotemporal dementia, a severe neurodegenerative disease.
The discovery comes from a study led by Silvia Di Angelantonio, a researcher at the Center for Life Nano- & Neuro-Science of the Italian Institute of Technology (IIT) and Sapienza University of Rome, in collaboration with Paola Bezzi from Sapienza University and the University of Lausanne.
Frontotemporal dementia typically develops at a relatively young age and affects key brain functions, such as behavior, language, and cognition. Currently, there are no effective treatments for this condition. In some inherited forms of the disease, mutations in the tau protein – crucial for proper neuron function – are responsible. When mutated, tau can accumulate abnormally in the brain, causing progressive and irreversible damage. This phenomenon is common to several neurodegenerative disorders known as tauopathies, including Alzheimer’s disease and frontotemporal dementia.
The research team demonstrated the effectiveness of bezafibrate – a well-known cholesterol-lowering medication – through lab testing on brain organoids, in countering certain typical markers of frontotemporal dementia.
To better understand the disease mechanisms, researchers used brain organoids – three-dimensional aggregates of nerve cells grown in the lab that can mimic some functions of the human brain. These organoids were derived from the cells of patients with frontotemporal dementia carrying tau mutations. As a result, the organoids replicated key features of the disease, such as loss of neuronal connections, decreased neural activity, and the accumulation of pathological tau protein.
Treatment with bezafibrate led to an increase in neuronal connectivity and partially restored functional activity in the organoids. Researchers also observed a reduction in the levels of pathological tau protein one of the main factors driving neurodegeneration.
“Bezafibrate,” explains Silvia Di Angelantonio, the lead author of the study and researcher at the Center for Life Nano- & Neuro-Science at IIT and Sapienza University of Rome, “was shown to support neuronal development while also reducing the buildup of pathological tau. These findings reveal early vulnerabilities in tauopathies and suggest that bezafibrate, already approved for other conditions, could be repurposed to treat these neurodegenerative diseases.”
As a next step, the team plans to refine their brain organoid models to more accurately replicate aging processes, including integrating immune system cells normally present in the brain. The goal is to develop increasingly comprehensive and representative disease models. In parallel, advanced electrophysiological techniques will be used to study neuronal communication and the formation of neural networks in greater detail.
“This approach,” concludes Di Angelantonio, “will guide us in identifying new therapeutic targets and developing effective treatments for devastating neurodegenerative diseases.”
The study, coordinated by the Italian Institute of Technology, was carried out in collaboration with Sapienza University of Rome, the University of Lausanne, and the joint IIT – D-TAils research lab.
