New research in mice and humans may help explain how sleep deprivation is linked to brain alterations associated with Alzheimer's disease.
Studies in mice and humans showed that lack of sleep increased levels of the protein tau which, along with the amyloid protein, builds up in the brain to cause the plaques and tangles thought to be responsible for Alzheimer's disease, according to David Holtzman, MD, of Washington University School of Medicine in St. Louis, and colleagues.
Sleeplessness was found to accelerate the spread of these toxic clumps through the brain in the mouse studies, they wrote in .
Earlier research by the same authors and others showed that the sleep-wake cycle regulates interstitial fluid (ISF) and cerebrospinal fluid (CSF) levels of amyloid-β.
"Amyloid is important in initiating disease, but the actual damage in the brain is probably due to the accumulation of tau," Holtzman told ֱ. "Normally tau protein is inside cells but there is more and more evidence suggesting that its spread to different parts of the brain is responsible for the progression of Alzheimer's disease."
Holtzman said other research led to the hypothesis that excessive nerve cell activity might precipitate the spread of tau protein.
"We knew that excessive wakefulness or sleep deprivation might accelerate neural activity," he said. "We wanted to see if it also exacerbated this tau pathology."
The researchers first measured tau levels in the hippocampal ISF of wild-type mice, which are largely nocturnal. They found that levels were low during the light period when the mice sleep approximately 60% of the time.
Tau levels were found to be roughly twice as high during the dark period, when the animals were awake and active roughly 70% of the time.
"The change in ISF tau between light and dark (approximately 90%) is greater than what we have previously observed with ISF amyloid-β (approximately 30%)," the researchers wrote. "Given this change, we asked whether acute sleep deprivation alters ISF tau."
Three hours after the beginning of the light period, mice were kept awake by manual stimulation. Sleep deprivation was found to induce a two-fold increase in ISF tau, which was paralleled by an increase in ISF lactate.
The researchers studied whether sleep deprivation changed tau expression in humans by examining data from a study they conducted in adults, ages 30 to 60, who were monitored with lumbar catheters during one night of normal sleep and one night of sleep deprivation. Sleep sessions were randomized and separated in time.
This study showed that sleep deprivation . By analyzing the same samples, the researchers found that CSF tau was increased by >50% in response to sleep deprivation and CSF tau levels significantly correlated with CSF amyloid-β levels.
The researchers assessed three additional proteins: neuronal 70 neurofilament light chain (NfL), synuclein, and astrocytic glial fibrillary acidic protein (GFAP).
They found that synuclein protein, which is a critical protein in Parkinson's disease, was increased by sleep deprivation, but no increase in NfL or GFAP was shown in CSF following sleep deprivation, suggesting some specificity in sleep/protein level interaction.
Like patients with Alzheimer's disease, Parkinson's patients often have sleep issues.
The researchers concluded that while the exact mechanism of tau release is unclear, "the changes observed here represent free, non-vesicle or exosome associated tau."
"It is also possible that decreased ISF tau clearance during wakefulness could contribute to the change observed," they wrote. "The fact that in human CSF we see changes in tau and synuclein but not all proteins following sleep deprivation argues that the changes are more likely due to increased release of certain proteins rather than changes in global ISF clearance."
Disclosures
The study was funded by the BrightFocus Foundation, Deutsche Forschungsgemeinschaft, the NIH, the Tau Consortium, the JPB Foundation, and the McDonnell Center for Systems Neuroscience at Washington University School of Medicine.
Holtzman disclosed relevant relationships with C2N Diagnostic, Denali, Genentech, Proclara, and AbbVie.
Primary Source
Science
Holth JK, et al "The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans" Science 2019.