Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, Finn MB, Manis M, Geerling JC, Fuller PM, Lucey BP, Holtzman DM. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. 2019 Feb 22;363(6429):880-884. Epub 2019 Jan 24 PubMed.

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  1. This fantastic collection of studies reveals several points worth emphasizing. The group finds tau (and to lesser extents Aβ and α-synuclein) responses to sleep loss to parallel lactate changes, while other proteins respond differently. This suggests that a mechanism beyond interstitial fluid clearance governs levels across sleep-wake. These proteins and peptides, which intriguingly tend to aggregate in neurodegenerative processes, increase not only with neuronal activity but metabolic challenge, presumably from sustained increased activity (as evidenced by the increased lactate).

    This metabolic challenge component of sleep loss may also contribute to the interesting pattern of tau spread that the group finds from the hippocampus all the way back to the locus coeruleus, a group of neurons particularly metabolically challenged by sleep loss. The hippocampus is highly connected and tau could have spread in numerous regions and even locally. Instead, it spreads to the rare neuron in the locus coeruleus and entorhinal cortex. These are areas where we have shown evidence of metabolic challenges caused by chronic sleep loss, including increased levels of oxidized tau and tau oligomers.

    Perhaps the most tantalizing point is that in rested conditions human tau shows little variance among participants, but in response to sleep loss the error bars expand, suggesting tau increases far more in some humans acutely in response to sleep loss than others. Are those humans more predisposed to developing a tauopathy, including Alzheimer’s? Only time will tell.

    View all comments by Sigrid Veasey

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