Sleep deprivation leads to non-adaptive alterations in sleep microarchitecture and amyloid-β accumulation in a murine Alzheimer model

Impaired sleep is a common aspect of aging and often precedes the onset of Alzheimer’s disease. Here, we compare the effects of sleep deprivation in young wild-type mice and their APP/PS1 littermates, a murine model of Alzheimer’s disease. After 7 h of sleep deprivation, both genotypes exhibit an increase in EEG slow-wave activity. However, only the wild-type mice demonstrate an increase in the power of infraslow norepinephrine oscillations, which are characteristic of healthy non-rapid eye movement sleep. Notably, the APP/PS1 mice fail to enhance norepinephrine oscillations 24 h after sleep deprivation, coinciding with an accumulation of cerebral amyloid-β protein. Proteome analysis of cerebrospinal fluid and extracellular fluid further supports these findings by showing altered protein clearance in APP/PS1 mice. We propose that the suppression of infraslow norepinephrine oscillations following sleep deprivation contributes to increased vulnerability to sleep loss and heightens the risk of developing amyloid pathology in early stages of Alzheimer’s disease. [Display omitted] •Sleep deprivation increases the power of NREM norepinephrine oscillation in WT mice•In contrast, sleep loss reduces the power of norepinephrine oscillations in APP/PS1 mice•Amyloid-β protein aggregates in APP/PS1 mice 24 h after sleep deprivation•The proteasomal pathway displays elevated upregulation upon sleep loss Cankar et al. report that sleep loss suppresses NREM norepinephrine oscillations in a murine model of Alzheimer’s disease along with a parallel buildup of amyloid-β. Thus, overexpression of amyloid-β inhibits recovery sleep and thereby slows glymphatic clearance after sleep deprivation. Norepinephrine oscillations persisted in wild-type mice after sleep deprivation.