Stem-cell microglia reveal two paths in frontotemporal dementia

In a laboratory at the University of Eastern Finland, researchers turned stem cells from frontotemporal dementia patients into microglia—the brain cells that help regulate inflammatory responses—and compared them with cells from healthy controls. The result: genetic and sporadic forms of the disease produced distinct microglial profiles.

One feature was shared. Microglia derived from all frontotemporal dementia patients had fewer intracellular lysosomal vesicles than microglia from healthy controls. Lysosomes are cellular compartments involved, among other functions, in protein metabolism, making their alteration a possible common thread across patients with different genetic backgrounds.

The C9-HRE cells—those carrying a C9orf72 hexanucleotide repeat expansion—were more active in two processes linked to lysosomal function: autophagy and phagocytosis. Professor Annakaisa Haapasalo says increased phagocytosis could lead to greater synapse loss, which could impair communication between neurons. Her team is still investigating that connection.

The sporadic-dementia cells showed a different pattern. Their gene expression differed significantly from both C9-HRE microglia and healthy controls, with reduced activity in pathways related to RNA, protein and energy metabolism. Genes involved in regulating the acute inflammatory response were altered in microglia derived from all frontotemporal dementia patients, while gene-expression changes in C9-HRE cells were comparatively modest.

And concretely? The findings suggest that microglial function may change differently in different patients. Further studies may need to distinguish between genetic and sporadic disease when examining the role of microglia. For now, the evidence comes from stem-cell-derived cells in the laboratory, and the link between altered phagocytosis and synapse loss remains under study.