Frontotemporal dementia (FTD) is a devastating brain disease that causes progressive changes in behavior, personality, language, and thinking. It is one of the leading causes of dementia in people under the age of 65, yet there are currently no treatments that can stop or slow disease progression. Many cases of inherited FTD are caused by mutations in the GRN gene, which lead to a deficiency of a critical protein called progranulin. This deficiency particularly affects microglia, the brain’s resident immune cells, which normally protect neurons, remove cellular waste, and maintain a healthy brain environment. When microglia lose progranulin, they become overactive, triggering chronic inflammation, damaging neurons, and disrupting normal brain function.
Our study, co-led by researchers from Blurton-Jones lab at UCI, Gan lab from Weill Cornell Medicine and Paz lab from Gladstone Institute, investigated whether transplanting healthy microglia could prevent the onset of FTD-GRN. Using human induced pluripotent stem cell (iPSC)-derived microglia, we transplanted healthy human cells into newborn, progranulin-deficient mice. We found that the transplanted cells successfully integrated throughout the brain, elevating progranulin levels to prevent neuronal dysfunction and behavioral abnormalities associated with the disease. Importantly, healthy microglia also protected surrounding brain cells, including neurons, astrocytes, and oligodendrocytes, demonstrating that correcting microglial dysfunction can have widespread therapeutic benefits.
These findings provide strong evidence for the central role that microglia play in the development of FTD and suggest that microglial cell replacement may represent a promising new therapeutic strategy for treating this currently incurable disease. Beyond FTD, this work may also have broader implications for other neurodegenerative disorders, including Alzheimer’s disease, where dysfunctional microglia contribute to disease progression. By developing therapies that restore the brain’s natural immune system, we hope to slow neurodegeneration and improve the quality of life for patients and their families. This work was published in the journal of Molecular Neurodegeneration (https://pubmed.ncbi.nlm.nih.gov/42464356/)
