This article investigates the role of tau–RNA complexes in neurodegenerative diseases, particularly Alzheimer's and related tauopathies. Tau protein, which normally supports microtubule assembly in neurons, becomes abnormally aggregated in conditions like Alzheimer's, forming neurofibrillary tangles. The study explores how tau binds RNA with high affinity, leading to significant disruption of tau's normal functions, including its interaction with microtubules. Using a series of molecular interaction studies, the authors demonstrate that tau's binding to RNA inhibits its ability to assemble microtubules and promotes the formation of pathological tau/RNA complexes, or oligomers. These tau oligomers may represent an early step in the formation of neurofibrillary tangles, a hallmark of Alzheimer's disease.

To further understand the role of tau–RNA interactions, the researchers developed a monoclonal antibody, TRC35, that specifically targets tau–RNA complexes. They found that TRC35 binds to pathological tau aggregates found in various tauopathies, including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, and Pick's disease. In animal models, tau expression alongside poly(A) RNA exacerbated tau-related neurodegeneration, supporting the idea that tau–RNA interactions are key drivers of disease progression. Interestingly, the accumulation of tau/RNA complexes in Alzheimer's disease models was significantly reduced in mice lacking the RNA-binding protein MSUT2, suggesting that RNA-binding proteins play a critical role in modulating tau aggregation.

The study highlights a previously underappreciated mechanism in tauopathies: the involvement of RNA in tau aggregation and neurodegeneration. It suggests that pathological tau/RNA interactions could be an important target for therapeutic intervention. By showing that tau binds RNA more readily than tubulin, the protein responsible for microtubule assembly, the research opens avenues for developing treatments aimed at disrupting tau–RNA interactions. This novel approach could help mitigate the toxic accumulation of tau that drives cognitive decline in Alzheimer's disease and related disorders.