Effects of early adulthood chronic sleep disruption on late life cognition, brain pathology, and microglial reactivity in the PS19 mouse model of tauopathy

Abstract

A bidirectional relationship has been proposed between sleep and Alzheimer’s disease pathology, such that disruption to sleep can lead to increases in the expression of tau or its phosphorylation. Over the long term, this can potentially lead to greater expression of neurofibrillary tangles and neurodegeneration. Neurodegenerative diseases characterized by tauopathy can often manifest with deficits in motor and spatial learning. We hypothesized that early adulthood chronic sleep disruption could accelerate tau pathology in a way that alters the trajectory of spatial and motor learning in later life. To test this hypothesis, we subjected early adulthood PS19 mice (MAPT P301S) and wildtype (WT) littermates to automated daily chronic sleep disruption (SD) vs. ad libitum sleep from 2 months to 4 months of age. A 4-day Barnes maze spatial learning task and 2-day rotarod motor learning task were conducted at 6, 8 and 10 months of age with subsequent brain neuropathological evaluation at 10–14 months prior to death. Contrary to our expectations, PS19 mice experiencing early adulthood SD displayed significantly improved spatial learning in comparison to ad libitum sleeping PS19 mice at 8 and 10 months of age, with no significant impact of early adulthood SD in WT mice. At 6 months, there was a significant impairment in offline motor change in PS19 mice compared to WT mice but without a significant effect of prior sleep condition. Early adulthood SD in PS19 mice led to increased hippocampal microglia density, without increased phagocytic microglia density, in late life compared to ad libitum sleep, suggesting sustained microglial proliferation by prior chronic SD. Similarly, TUNEL positive cells were also increased with early adulthood SD in PS19 mice, suggesting persistent DNA damage in late life. However, neither tau pathology nor histological markers for neurodegeneration were significantly different between early adulthood sleep conditions in PS19 mice tested at later life. Thus, the improvement in spatial learning in late life following early adulthood chronic SD in PS19 mice would seem disentangled from an effect on tauopathy or neurodegeneration, but whether the behavioral consequence is related to the observed changes in hippocampal microglial density remains to be mechanistically linked.