New understanding of how sleep, Tau and dementia interrelate
Research has shown that Tau protein(opens in new window), when found in the brain of people living with Alzheimer’s disease, accumulates in aggregates such as tangles and also has many more phosphosites(opens in new window) compared with Tau from healthy subjects. Intriguingly, there seems to be an overlap between those phosphosites found in people living with Alzheimer’s disease and the ones evoked by sleep. The sleepyTau(opens in new window) researcher Marieke Hoekstra(opens in new window), based at the Flanders Institute for Biotechnology(opens in new window) (VIB) in Belgium, wanted to dig more deeply into the relationship between sleep and Tau phosphorylation. “During sleep, mammalian brain temperature decreases by 1-2 °C. Even though the drop is small it suffices to activate temperature-sensitive pathways that can alter brain function, including Tau phosphorylation,” she explains. If we can understand what the function of phosphorylated Tau (pTau) is when we are asleep, we’ll have a first clue how, overtime, pTau can become associated with disease. So the sleepyTau project, run out of the Laboratory of Neuronal Communication led by Patrik Verstreken(opens in new window), set out to examine sleep-dependent rewiring in the hippocampus, a brain region essential for memory consolidation. The hippocampus is also one of the first regions to become impaired in Alzheimer’s disease.
Insights into the sleeping brain and the action of Tau
To gain an insight into the Tau-dependent strength of neuronal connections in the hippocampus, sleepyTau used a technique in which brain slices from mice were placed on a multi-electrode array(opens in new window). “With the electrodes in this set-up, we stimulated neurons in one place and measured how neurons downstream, those to which the stimulated neurons are connected, responded to this stimulation,” adds Hoekstra, coordinator of the Marie Skłodowska-Curie Actions(opens in new window) funded project. The team found that the response from neurons downstream is much stronger when mice have slept well. Intriguingly, if mice slept well but their levels of the Tau protein are reduced, the response from the neurons downstream is not as good. “This is a clear indication in the direction of our hypothesis that Tau, and presumably pTau, has a function during sleep,” notes Hoekstra. This suggests that Tau contributes to sleep-dependent neuronal communication. The research is related to the DIVE into AD project which is also funded by the EU and investigating the contribution of Tau in dementia.
Intriguing overlap between Tau phosphosites found in sleep and neurodegeneration
Hoekstra feels the overlap between sleep-evoked Tau phosphosites and those found in neurodegeneration is so pronounced that it begs the question: What is the physiological function of those pTau sites in sleep? Insights into this process can provide clues as to how pTau becomes associated with pathology, where Tau could, beyond forming aggregates, also execute its physiological function in overdrive which could contribute to neuronal malfunctioning. Together with fellow researcher Ryan Trouvé, in the lab of Patrik Verstreken(opens in new window), Hoekstra is currently setting up a model to test the functional implications of these pTau sites. Other research groups had already discovered that Tau phosphorylation increases during sleep. sleepyTau broke new ground by realising that this could in fact have a physiological role and by developing this proposition into their own, unique research angle. As Hoekstra says: “By understanding how nature’s functional mechanisms can start to work against us, similar to cell growth breaking out of control in cancer, we can ultimately develop new strategies to, at least, slow down disease progression, if not cure it.”
