Nauk1 Inhibition as a Treatment for Tauopathies

Tauopathies are conditions in which altered forms of tau protein accumulate into solid deposits in the brain. How this causes cell death and dysfunction is comparatively poorly understood, or at least well debated, but researchers are making inroads into mapping the relevant mechanisms. As is the case for other types of misfolded or altered protein that show up in aged tissues, it isn't so much the protein itself, but rather aspects of the surrounding processes that are the cause of harm. Still, getting rid of the altered tau would be a good way to reduce all of these problems, even in absence of understanding: young tissues don't have tau and work just fine, old tissues do have it and don't work so well, and the logic moves forward from there. If in doubt, identify the fundamental differences and remove them. Alzheimer's disease is the the most familiar of tauopathies, for all that much of the research community is focused on the form of amyloid that accumulates in Alzheimer's patients. Amyloid-β in Alzheimer's is another example of a protein that forms solid deposits and is accompanied by a surrounding set of mechanisms that harm cells when the amyloid is present in large amounts. For all that amyloid-β and tau are completely different, there are many high level similarities in their separate relationships with neurodegenerative conditions. It is becoming clear that the neurofibrillary tangles of tau in Alzheimer's disease are just as important as the amyloid, though the full story of how the disease starts and progresses, and how its components interact with one another, has yet to be written.

Everyone ends up with tau and amyloid in the brain to some degree as they age; even those that live to a very late age accumulate a fair amount of the stuff. The interesting question is why some people end up with so very much more than others and slip into full blown dementia as a result. Based on the clearly established risk factors, which are much the same as those for most age-related conditions, being obesity, lack of exercise, and so forth, the triad of chronic inflammation, cardiovascular health, and metabolic syndrome are important. As for other age-related conditions, it seems to me that one of the best courses to produce near term results is to aim at the production of safe methods to clear out amyloid and tau. The research community is working hard on the former, with most of the effort going towards immunotherapies that are just now starting to produce meaningful results, but tau clearance is a fair way behind in funding and progress.

Behind doesn't mean lacking in paths forward, however, as illustrated here. The research presented below isn't clearance, however, but rather a reduction in the pace of creation of unwanted tau, achieved through mechanisms yet to be explored in great depth. For preference we'd want to see a therapy that removed tau without altering the operation of cellular metabolism - this is why immunotherapies are attractive, putting immune cells to work on the problem of clearing out the junk in a selective way, while other cells keep on doing exactly what they were doing beforehand. The problem with therapies that only slow the accumulation of damage or metabolic waste rather than removing it outright is that they are inefficient and limited in the scope of the good they can do. You have to keep taking the treatment on an ongoing basis, and you still end up in the same place in the end, just later. A therapy that removed tau could be undergone once every few years, or even less frequently, repeated only as needed to prevent pathological levels of tau from ever arising. One of the fundamental and very important problems in medicine today is that far too much research and development is focused on slowing damage rather than repairing damage.

Study reveals potential new strategy to prevent Alzheimer's disease

"Scientists in the field have been focusing mostly on the final stages of Alzheimer's disease. 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.

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 inhibited about 600 kinases one by one and found one, called Nuak1, whose inhibition consistently resulted in lower levels of tau in both human cells and fruit flies. 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. 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."

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. 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."

Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model

Many neurodegenerative proteinopathies share a common pathogenic mechanism: the abnormal accumulation of disease-related proteins. As growing evidence indicates that reducing the steady-state levels of disease-causing proteins mitigates neurodegeneration in animal models, we developed a strategy to screen for genes that decrease the levels of tau, whose accumulation contributes to the pathology of both Alzheimer disease (AD) and progressive supranuclear palsy (PSP). Integrating parallel cell-based and Drosophila genetic screens, we discovered that tau levels are regulated by Nuak1, an AMPK-related kinase. Nuak1 stabilizes tau by phosphorylation specifically at Ser356. Inhibition of Nuak1 in fruit flies suppressed neurodegeneration in tau-expressing Drosophila, and Nuak1 haploinsufficiency rescued the phenotypes of a tauopathy mouse model. These results demonstrate that decreasing total tau levels is a valid strategy for mitigating tau-related neurodegeneration and reveal Nuak1 to be a novel therapeutic entry point for tauopathies.


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