TYK2 inhibition may offer new strategy to reduce tau toxicity in Alzheimer’s

Researchers from Baylor College of Medicine, the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, and collaborating institutions discovered that the enzyme TYK2 converts the normal protein tau into a protein that accumulates in the brain and contributes to cancer. to the development of Alzheimer’s disease. disease in animal models. Published in Nature Neurosciencethe study suggests that partially restricting TYK2 could be a strategy to reduce tau levels and toxicity.

“Many studies have shown that the accumulation of tau in neurons and glial cells in the brain is a key feature of Alzheimer’s disease and at least 24 other neurological diseases,” said first author Dr. Ji-Yoen Kim, assistant professor of molecular and human medicine. genetics at Baylor in Dr.’s laboratory. Huda Zoghbi. Zoghbi, the corresponding author of the work, is a Distinguished Service Professor at Baylor, director of the Duncan NRI and an investigator of the Howard Hughes Medical Institute (HHMI).

Previous studies have shown that tau is chemically modified in disease, mainly by the addition of extra phosphate to the tyrosine groups in the protein, and that these changes play a crucial role in regulating the accumulation of tau.

The Zoghbi lab had previously identified TYK2 – an enzyme that adds phosphate to tyrosine groups – as a potential regulator of tau levels and that knocking down the TYK2 gene reduced tau levels in human cells. In the current study, the team delved deeper into how TYK2 transforms tau into a protein that aggregates and propagates to neighboring cells and accumulates in tangles within cells, influencing the development of tau-driven neurodegeneration.

Working with human cells and animal models of tau-induced dementia, the researchers are the first to show that TYK2’s modifications to tau contribute to tau-mediated diseases. “We found that TYK2 adds phosphate groups to tau at a specific location on the protein identified as Tyrosine 29,” Kim said. “This modification stabilizes tau levels in human cells and mouse neurons by making it resistant to autophagy, a cellular process important for protein clearance,” Kim said. “Impervious to clearance, modified tau accumulates in the brain.”

The finding that TYK2 enhances tau aggregation suggested that manipulating TYK2 could help regulate tau aggregation and its consequences. The team tested the effect of partially reducing TYK2 in two mouse models and found that this was enough to reduce tau levels and reduce its accumulation. “While much work is needed, our findings suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau accumulation and toxicity,” Kim said.

In this regard, we are encouraged by the fact that others have developed TYK2 inhibitors that have been tested in humans for other indications. Studies are needed to see if these inhibitors actually get to the brain and reduce tau levels to investigate their potential effects in Alzheimer’s disease and tau-induced dementias.”

Dr. Huda Zoghbi, corresponding author

Bakhos Tadros, Yan Hong Liang, Youngdoo Kim, Cristian Lasagna-Reeves, Jun Young Sonn, Dah-eun Chloe Chung, Bradley Hyman, and David M. Holtzman also contributed to this work. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Indiana University School of Medicine, Harvard Medical School, and Massachusetts General Hospital, Washington University in St. Louis and Howard Hughes Medical Institute.

This work was funded by JPB Foundation, HHMI, Eunice Kennedy Shriver National Institute of Child Health and Human Development NIH grant P50HD103555, and NIH/NINDS grant R01NS119280.