Taming Overactive Microglial Pathway Could Slow Neurodegenerative Disease

Inhibiting a signaling pathway in immune cells residing in the brain may calm brain inflammation and slow disease progression in Alzheimer’s and some other neurodegenerative disorders, according to a new study by Weill Cornell Medicine researchers.

Abnormal aggregates, or “tangles” of neuronal protein tau and brain inflammation—especially via the activation of immune cells in the brain called microglia—are two common features of neurodegenerative diseases. Tau tangles are found inside neurons in affected brain areas in Alzheimer’s, Parkinson’s, Pick disease, progressive supranuclear palsy, frontotemporal dementia and other neurodegenerative diseases.

Experiments have shown that tangles, when injected into animal brains, can seed the formation of new tangles, creating a chain-reaction in which the tangles spread to other brain regions.  Prior studies have also suggested that tau tangles can interact with microglia, in a way that drives the microglia into an inflammatory, disease-associated state. In this inflamed state, the microglia, which normally try to consume the tau tangles, become relatively inefficient at doing so. Much of the tau ends up being not digested but, rather, disgorged from the microglia, in forms that tend to seed new tangles.

In a recent issue of Nature Communications, the Weill Cornell team reports evidence from cell culture and mouse experiments that tau tangles push microglia into this disease-linked inflammatory state mainly by activating the NF-κB signaling pathway within them. In an Alzheimer’s mouse model with tau-tangle mainly driven by seeded tau, they showed that keeping the NF-κB pathway overactive in microglia enhanced the seeding and spread of tangles, which propel further NF-κB activation. By contrast, shutting off NF-κB blocked this vicious cycle, and markedly lessened the spread of the tangles.

In another tau mouse model, with tau tangle formed in aged neurons, the researchers showed that the inactivation of microglial NF-κB shifted the microglia almost entirely out of their inflammatory, disease-associated state, restoring a much more normal cell appearance and pattern of gene activity. This shift, which suppresses microglia from disgorging toxic tau seeds, strikingly, prevented key cognitive/memory deficits the mice normally develop in this model.

“Our findings suggest restraining overactive NF-κB may be a good therapeutic strategy in Alzheimer’s and other tau-mediated neurodegenerative diseases,” says senior author Dr. Li Gan, director of the Helen and Robert Appel Alzheimer’s Disease Research Institute and the Burton P. and the Judith B. Resnick Distinguished Professor in Neurodegenerative Diseases in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.

The new findings suggest that future drugs taming overactive microglial NF-κB signaling might fare better, Dr. Gan said. Her lab is now following up with further research to detail more precisely how microglial NF-κB signaling, which affects the activities of at least hundreds of other microglial genes, impairs neurons and leads to cognitive and memory deficits. The researchers will investigate how to restrain specific aspects of overactive NF-κB signaling without affecting the normal function of brain’s immune cells.