Study reveals potential new treatment target Nuak1 kinase to prevent accumulation of protein in early Alzheimer’s disease

Taking a pill that prevents the accumulation of toxic molecules in the brain might someday help prevent or delay Alzheimer’s disease, according to scientists at Baylor College of Medicine, Texas Children’s Hospital and Johns Hopkins University School of Medicine.

The study, published today in Cell Press journal Neuron, took a three-pronged approach to help subdue early events that occur in the brain long before symptoms of Alzheimer’s disease are evident. The scientists were able to prevent those early events and the subsequent development of brain pathology in experimental animal models in the lab.

Brain section from mouse carrying the dementia-causing P301S mutation
in human tau shows accumulation of tau neurofibrillary tangles (in dark brown,
left). When Nuak1 levels are decreased by 50 percent (P301S/Nuak1+/-; right),
fewer tau tangles accumulate. Credit: The Zoghbi lab/Baylor College of Medicine

“Scientists in the field have been focusing mostly on the final stages of Alzheimer’s disease,” said first author Dr. Cristian Lasagna-Reeves, postdoctoral fellow in the Zoghbi lab. “Here we tried to find clues about what is happening at the very early stages of the illness, before clinical irreversible symptoms appear, with the intention of preventing or reducing those early events that lead to devastating changes in the brain decades later.”

The scientists reasoned that if they could find ways to prevent or reduce tau accumulation in the brain, they would uncover new possibilities for developing drug treatments for these diseases.
Cells control the amount of their proteins with other proteins called enzymes. To find which enzymes affect tau accumulation, the scientists systematically inhibited enzymes called kinases.  “We inhibited about 600 kinases one by one and found one, called Nuak1, whose inhibition resulted in reduced levels of tau,” said Zoghbi, who is also an investigator at the Howard Hughes Medical Institute.

The scientists screened the enzymes in two different systems, cultured human cells and the laboratory fruit fly. Screening in the fruit fly allowed the scientists to assess the effects of inhibiting the enzymes in a functional nervous system in a living organism.

“We found one enzyme, Nuak1, whose inhibition consistently resulted in lower levels of tau in both human cells and fruit flies,” said Zoghbi. “Then we took this result to a mouse model of Alzheimer’s disease and hoped that the results would hold, and they did. Inhibiting Nuak1 improved the behavior of the mice and prevented brain degeneration.”  Brain section from mouse carrying the dementia-causing P301S mutation in human tau shows accumulation of tau neurofibrillary tangles (in dark brown, left). When Nuak1 levels are decreased by 50% (P301S/Nuak1+/-; right), fewer tau tangles accumulate.

 “Confirming in three independent systems – human cells, the fruit fly and the mouse – that Nuak1 inhibition results in reduced levels of tau and prevents brain abnormalities induced by tau accumulation, has convinced us that Nuak1 is a reliable potential target for drugs to prevent diseases such as Alzheimer’s,” said Zoghbi. “The next step is to develop drugs that will inhibit Nuak1 in hope that one day would be able to lower tau levels with low toxicity in individuals at risk for dementia due to tau accumulation.”

Publication: Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model.Authors: Cristian A. Lasagna-Reeves et. al.,
DOI: http://dx.doi.org/10.1016/j.neuron.2016.09.022
Journal: Neuron
Research funding: This work was supported by the Howard Hughes Medical Institute, the Robert A. and Renee E. Belfer Family Foundation, the Hamill Foundation, the Chapman Foundation, and the National Institutes of Health. Support also was provided by the Texas Alzheimer’s Research and Care Consortium-Investigator Grant Program, the Darrel K. Royal Foundation grant, the Canadian Institutes of Health Research Fellowship, the Mass Spectrometry-Proteomics Core Laboratory (MS-PCL) and the confocal microscopy, neuroconnectivity and mouse behavioral cores of the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center , the Johns Hopkins University Morris Udall Parkinson’s Disease Center of Excellence and Alzheimer Disease Research Center.
Adapted from press release by Baylor College of Medicine.