A potential target for the treatment of Alzheimer’s? Researchers discover new immune response pathway – Endpoints News


Most Alzheimer’s drugs, including Biogen’s aducanumab (Aduhelm) and Eli Lilly’s donanemab, target amyloid plaques, clumps of misfolded proteins that accumulate in the brain, which are a hallmark of Alzheimer’s disease. However, researchers at Weill Cornell have discovered another immune response pathway that could be a potential target for new therapies.

In addition to amyloid plaques, patients with Alzheimer’s disease also experience the buildup of tau proteins inside their neurons. In healthy neurons, tau proteins help stabilize microtubules that carry neurotransmitters from one end of the neuron to the other. However, in patients with Alzheimer’s disease, tau proteins clump together and form tangles in neurons that block this transport process.

In the study published in Nature Communication and led by Li Gan, the researchers found that in mice seeded with these tau tangles, a specific microglial pathway, NF-κB, can accelerate the seeding and spread of said tau tangles. On the other hand, inactivation of the NF-κB pathway reversed tau-mediated changes, rescuing spatial learning and memory deficits in mice.

Previous studies have suggested that microglia, central nervous system immune cells, and tau proteins influence each other in Alzheimer’s disease. While healthy microglia eat up all the extra tau proteins, in Alzheimer’s disease they instead flare up and spread and seed new tau tangles. The accumulation of tau tangles and the resulting synaptic dysfunction lead to “tauopathies”, a group of neurodegenerative diseases, including Alzheimer’s disease.

Previous research has also shown that the NF-κB pathway is activated by the formation of amyloid plaques, but the role of the immune pathway in the less studied formation of tau tangles was until now unclear.

Gan and colleagues showed that in mice seeded with tau, activation of NF-κB in microglia resulted in more tau tangles, which then turned around and further activated the NF-κB pathway. In contrast, NF-κB inhibition in a different mouse model rescued learning and memory deficits, “suggesting that NF-κB hyperactivation drives tau toxicity in neurons,” wrote the Research Team.

“Taken together, our work shows that microglial NF-κB acts downstream of tau pathology and directly induces toxic effects on cognition, highlighting the potential of blocking maladaptive microglial responses instead of eliminating tau aggregates as a therapeutic strategy. to treat tauopathy,” the researchers. mentioned.

Although targeting NF-κB has not yet garnered widespread interest, a handful of biotechs have launched different efforts to treat Alzheimer’s disease by manipulating microglia, including Atlas-backed Vigil Neuroscience and partner Alector from GSK.


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