Post by Thomas Brown

What’s the science?

Tau, a protein which accumulates in the brain in Alzheimer’s, is one of the primary pathologies of Alzheimer’s disease and correlates well with disease progression. Previous studies have shown that tau inclusions often start in particular areas of the brain, eventually spreading throughout the brain over time. One of these brain regions is the locus coeruleus (LC) (a small brainstem nucleus) known to regulate wakefulness and stress by releasing norepinephrine in the brain. Locus coeruleus neurons are also known to be damaged during chronic sleep disruption, however, the role of chronic sleep disruption in tau protein aggregation in the brain remains unknown. This week in the The Journal of Neuroscience Zhu and colleagues assessed whether chronic sleep deprivation in a mouse model of tauopathy leads to an increased progression of tau pathology.

How did they do it?

The authors used P301S mice, a strain of transgenic mice that express human tau. In this mouse, a human version of the MAPT disease-associated P301S mutation is inserted into chromosome 3 of the mouse, which results in human P301S tau being expressed. In P301S mice, the authors induced one of two models of chronic sleep disruption. The first model involved placing the mice in a new environment during a lights-on period (a period when the mouse normally sleeps) while the second involved placing the mouse cage upon a rotor, repeatedly nudging mice awake resulting in increasing arousals. The use of two different methods allowed the authors to determine whether mice were simply reacting to a new environment versus responding to sleep deprivation. The chronic sleep disruption mice were compared to a control group of “rest” mice. After chronic sleep deprivation the mice were given a number of behavioural tests over time to assess motor impairment and spatial memory. The locus coeruleus and amygdala (the brain’s ‘fear centre’) were then examined for tau protein accumulation, gliosis, and signs of neuronal death.

What did they find?

The authors found that by 7 months of age (after 3 months of chronic sleep disruption) P301S mice with an irregular sleep pattern performed worse than P301S “rest” mice which had been able to rest. This motor impairment worsened over time between 5 and 7 months. In an open field test, where the locomotor activity of mice in a novel environment is monitored, mice with sleep disruption showed heightened activity in the first two minutes, which could denote anxiety. The authors also utilized the ‘Novel object recognition test’ as a spatial memory test, in which a mouse is habituated to an object, and then presented with a familiar and an unfamiliar (i.e. novel) object. A healthy mouse will normally inspect the novel item. P301S mice that underwent chronic sleep disruption had a reduced preference for the novel object, indicating that their memory was impaired compared to rested mice. Immunohistochemical analysis showed an increase in tau protein accumulation in mice with chronic sleep disruption, including soluble and tangled tau, as well as increased neuronal death in both the amygdala and the locus coeruleus. Additionally, there was also increased activation of glial cells in the mice with disrupted sleep at 7 months, which is a common finding in many neurodegenerative conditions. Taken together, these results indicate that in a model of tauopathy, chronic sleep disruption earlier in life can lead to increased accumulation of tau as well as motor and cognitive impairments.