Chronic sleep disruption advances the temporal progression of tauopathy in P301S mutant mice

Abstract

Brainstem locus ceruleus neurons (LCn) are among the first neurons across the lifespan to evidence tau pathology, and LCn are implicated in tau propagation throughout the cortices. Yet, events influencing LCn tau are poorly understood. Activated persistently across wakefulness, LCn experience significant metabolic stress in response to chronic short sleep (CSS). Here we explored whether CSS influences LCn tau and the biochemical, neuroanatomical, and/or behavioral progression of tauopathy in male and female P301S mice. CSS in early adult life advanced the temporal progression of neurobehavioral impairments and resulted in a lasting increase in soluble tau oligomers. Intriguingly, CSS resulted in an early increase in AT8 and MC1 tau pathology in the LC. Over time tau pathology, including tangles, was evident in forebrain tau-vulnerable regions. Sustained microglial and astrocytic activation was observed as well. Remarkably, CSS resulted in significant loss of neurons in the two regions examined: the basolateral amygdala and LC. A second, distinct form of chronic sleep disruption, fragmentation of sleep, during early adult life also increased tau deposition and imparted early neurobehavioral impairment. Collectively, the findings demonstrate that early life sleep disruption has important lasting effects on the temporal progression in P301S mice, influencing tau pathology and hastening neurodegeneration, neuroinflammation, and neurobehavioral impairments.