Study reveals potential new strategy to prevent Alzheimer’s disease
“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.”
“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.”
Scientific studies like this one that uncover basic biological mechanisms of disease make it possible to develop new strategies to prevent or treat diseases such as Alzheimer’s, Parkinson’s or dementia.
In the future it might be possible to treat people at risk for Alzheimer’s disease by keeping tau low. Think of how taking drugs that lower cholesterol has helped control the accumulation of cholesterol in blood vessels that leads to atherosclerosis and heart disease.
“When people started taking drugs that lower cholesterol, they lived longer and healthier lives rather than dying earlier of heart disease,” said Zoghbi. “Nobody has thought about Alzheimer’s disease in that light. Tau in Alzheimer’s can be compared to cholesterol in heart disease. Tau is a protein that when it accumulates as the person ages, increases the vulnerability of the brain to developing Alzheimer’s. So maybe if we can find drugs that can keep tau at levels that are not toxic for the brain, then we would be able to prevent or delay the development of Alzheimer’s and other diseases caused in part by toxic tau accumulation.”
“Just like people now take their cholesterol-lowering medications, people in the future could be taking medications to keep tau levels low and prevent the development of Alzheimer’s disease,” said Lasagna-Reeves.
Other contributors to this work include María de Haro, Shuang Hao, Jeehye Park, Maxime W.C. Rousseaux, Ismael Al-Ramahi, Paymaan Jafar-Nejad, Luis Vilanova-Velez, Lauren See, Antonia De Maio, Larissa Nitschke, Zhenyu Wu, Juan C. Troncoso, Thomas F. Westbrook and Jianrong Tang.
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 grants NIH/NINDS R01 NS027699-17, NIH/NINDS 3R01 NS027699-25S1 and 1K22NS092688-0. 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 (201210MFE-290072-173743), 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 (1U54 HD083092), the Johns Hopkins University Morris Udall Parkinson’s Disease Center of Excellence (NINDS P50 NS38377) and Alzheimer Disease Research Center (NIA P50 AG05146).