Low Brain Protein Levels Associated with Neurodegeneration

The study, published in Science Translational Medicine, reveals the molecular mechanism by which the mutated forms of this protein prevent the amyloid waste cleaning process from functioning correctly and detects a lower level of the functional form of this protein in the cerebrospinal fluid of people suffering from Alzheimer's disease and frontotemporal dementia.

The TREM2 gene is expressed mainly in the microglia, brain cells in charge of phagocytosis and of eliminating cell waste which accumulates in this organ, such as amyloid fibres and other protein aggregates. For some years now it has been known that mutations in TREM2 cause rare and aggressive neurodegenerative diseases known as Nasu-Hakola and FTD-like syndrome. Nevertheless, recent genetic studies have linked other less aggressive mutations in this gene to a higher risk of suffering from other more common neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.

In this study, led by Professor Christian Haass and DR Gernot Kleinberger from the Ludwig Maximilian University of Munich, the role played by TREM2 in the microglia when regulating its function as a phagocyte was revealed.

The study was conducted in two phases. In the first, carried out with microglial cell cultures, scientists observed that when mutated forms of TREM2 are expressed, the protein does not reach the cell membrane and the cells lose their ability to clean the residues accumulated in the brain.

In the second phase, researchers observed in the analyses carried out that patients with Alzheimer's disease or frontotemporal dementia tended to have low levels of TREM2 in their cerebrospinal fluid, while patients with FTD-like syndrome completely lacked this protein.

“Although we must still continue researching, these results suggest that the TREM2 protein plays a fundamental role in the elimination of amyloids and other protein aggregates and its malfunctioning can accelerate neurodegenerative processes. It could also be a useful indicator of neurodegenerative diseases", explains Marc Suárez-Calvet, pre-doctoral researcher at the UAB and participant in the study.

Persons with reduced levels of the TREM2 protein could be at greater risk of developing neurodegenerative diseases such as Alzheimer's disease or frontotemporal dementia, according to an international study which included the participation of the UAB and the IBB Sant Pau.

The stimulation of TREM2 functions could be a useful strategy when fighting neurodegenerative diseases, the study indicates. “It would be good to continue with the research and observe if acting on the TREM2 to restore or increase its activity could be effective in treating different neurodegenerative pathologies”, concludes Albert Lleó, IBB researcher and lecturer at the UAB Department of Medicine.

Also participating in the study were IBB researchers Daniel Alcolea and Juan Fortea, as well as the research team led by Dr José Luís Molinuevo, from the Clínic Hospital of Barcelona.