How does the role of NUAK1 tau phosphorylation differ within mouse and human brains, and why could inhibiting this enzyme open the door to future therapeutics within Alzheimer’s disease research?
A new paper published by the journal Acta Neuropathologica has highlighted a possible driver of Alzheimer’s disease.
Alzheimer’s disease is the most common form of dementia worldwide, encompassing a range of symptoms such as memory loss, that contributes to cognitive decline within individuals. Since age is the greatest risk factor to developing the disease, it is most widespread in people aged over 65. With more people living longer due to advances in global healthcare systems, the number of people diagnosed with Alzheimer’s disease is set to increase. As there is no cure, recent advancements in disease-modifying treatments are the only possible therapies shown to slow down the progression of the disease.
"Phospho-tau 356 appears to correlate with Alzheimer’s disease progression"
Neurons within Alzheimer’s disease fail to communicate properly due to a build up of amyloid plaques and tau tangles, resulting in neuronal cell death. These tau tangles are made up of hyperphosphorylated tau. Enzymes, known as kinases, can regulate the turnover of tau by phosphorylating the protein. One kinase in particular, named NUAK1, is responsible for generating a type of phospho-tau 356.
Recently, researchers at the UKDRI University of Edinburgh used high resolution imaging to find that levels of phospho-tau 356 correlated with Alzheimer’s disease progression within human post-mortem brains. It was noted that post-mortem brains at later disease staging had higher levels of phospho-tau 356. Moreover, phospho-tau 356 was found within the between the synapses of neurons in post-mortem Alzheimer’s disease patients, near neurofibrillary tangles, possibly disrupting cell-to-cell communication. Therefore, phospho-tau 356 appears to correlate with Alzheimer’s disease progression.
Next, scientists blocked the action of NUAK1 by using an inhibitory drug. By using mouse brain slice cultures, the overall tau levels decreased both in the neuron and within the synapse itself. However, when used on valuable left-over human brain tissue from tumour removal surgery, the drug demonstrated more specificity compared to mice brain slices, by selectively lowering phospho-tau 356 levels alone.
Overall, these findings have determined that phosphor-tau 356 correlates with Alzheimer’s disease progression, with higher levels of phospho-tau associated with more severe Alzheimer’s disease cases post-mortem. Thus, phospho-tau 356 could be a future therapeutic target for Alzheimer’s disease via inhibiting NUAK1 enzyme activity. Finally, this study highlighted differences in tau turnover from NUAK1 activity within both mouse and human brain tissue; indicating the importance of translating animal research into human therapies.
This article was written by Catherine Turnbull and edited by Julia Dabrowska. Interested in writing for WiNUK yourself? Contact us through the blog page and the editors will be in touch!
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