Researchers from Baylor College of Medicine, the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, and collaborating institutions have made a significant discovery regarding the enzyme TYK2 and its role in Alzheimer's disease. The study, published in Nature Neuroscience, reveals that TYK2 transforms the protein tau into a form that accumulates in the brain, contributing to Alzheimer's development in animal models. The research suggests that partially restraining TYK2 could reduce tau levels and its associated toxicity.
"Many studies have shown that the accumulation of tau in neurons and glial cells in the brain is a main characteristic of Alzheimer’s disease and at least 24 more neurological diseases," stated Dr. Ji-Yoen Kim, first author and assistant professor at Baylor College of Medicine. Dr. Huda Zoghbi, corresponding author and director of Duncan NRI, emphasized their lab's prior identification of TYK2 as a regulator of tau levels.
Previous research indicated that chemical modifications involving extra phosphate addition to tyrosine groups play a crucial role in tau accumulation. In this new study, researchers demonstrated how TYK2 modifies tau to promote aggregation within cells, impacting neurodegeneration.
The team showed for the first time that TYK2 adds phosphate groups to tau at Tyrosine 29. "This modification stabilizes tau levels in human cells and mouse neurons by making it resistant to autophagy," said Kim. As a result, modified tau accumulates in the brain due to its resistance to clearance.
The findings suggest manipulating TYK2 might regulate tau aggregation and its effects. By partially reducing TYK2 activity in two mouse models, researchers observed decreased tau levels and reduced accumulation. "Although much work is needed, our findings suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau accumulation and toxicity," Kim added.
Dr. Zoghbi mentioned existing TYK2 inhibitors tested for other conditions could potentially lower brain tau levels if proven effective against Alzheimer's disease-related dementias: "Studies are needed to see if these inhibitors indeed get into the brain."
Contributors include Bakhos Tadros, Yan Hong Liang, Youngdoo Kim, Cristian Lasagna-Reeves among others from institutions such as Indiana University School of Medicine; Harvard Medical School; Massachusetts General Hospital; Washington University St Louis alongside Howard Hughes Medical Institute affiliations.
Funding came from various sources including JPB Foundation HHMI Eunice Kennedy Shriver National Institute Child Health Human Development NIH grant P50HD103555 NIH/NINDS grant R01NS119280 Ting Tsung Wei Fong Chao Foundation
