Scientists have identified that mutations in a protein commonly linked to frontotemporal dementia (FTD) result in obsessive-like behaviors. They linked these behaviors to immune pathways, implicating that targeting key components of the immune system could be a new therapeutic strategy for FTD.

The study was published in the journal Proceedings of the National Academy of Sciences.

FTD is a common form of dementia in people under 65 years of age. Its symptoms include marked disturbances in language and debilitating changes in behavior, including loss of social awareness and impulse control. There is no cure for FTD, but by better understanding what underlies the symptoms of the disease, researchers believe that they will move closer to a cure.

Research has already shown that mutations in the protein progranulin are linked to some forms of FTD, but how progranulin is involved in the changes to behavior was not clear. The researchers had some hints from previous work: mice lacking progranulin groom themselves excessively, similar to obsessive behaviors seen in FTD patients who have mutated progranulin. Those mutations also result in too much of an inflammatory signal called TNFa, and FTD patients have an increased risk of autoimmune disorders in which TNFa has been implicated. From these key pieces of information, the research team wondered how the immune system, and TNFa in particular, might be involved in FTD.

They began their study by using genetic methods to delete the gene for TNFa in mice that lacked progranulin. Interestingly, removing TNFa stopped the excessive grooming.

They then examined resident immune cells in the brain called microglia. These cells use their long processes to “feel around” neurons and their surroundings to ensure a proper “working environment.” If they detect a damaged neuron or an infection, they become mobilized to take up neuronal debris or pathogens, and they secrete chemical signals to attract other microglia to help deal with the problem.

The scientists used genetic methods to delete progranulin specifically from microglia, which induced excessive self-grooming in the mice. This finding established, for the first time, that microglia regulate obsessive behaviors. Those behaviors could be prevented by inactivating a master regulator of the immune system, NF-kB, in microglia.

Reducing NF-kB activity in immune cells yielded another important result. Mice lacking progranulin are not as social as normal mice, and this feature is quite similar to a behavior in FTD patients, who become socially withdrawn. Reducing NF-kB levels in immune cells not only reduced excessive grooming, but it also improved the social behavior of the mice lacking progranulin. This suggests that NF-kB may be at the center of the behavioral abnormalities observed in FTD.

Paper: “Microglial NFκB-TNFα hyperactivation induces obsessive–compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia”
Reprinted from materials provided by Gladstone Institutes.