Chronic neuropeptide S treatment improves sleep architecture and reduces Aβ-related pathology in APP/PS1 mice

Background Sleep disturbances frequently occur in Alzheimer’s disease (AD). Although neuropeptide S (NPS) promotes wakefulness through the widely expressed NPS receptor (NPSR), its role in AD-related sleep dysregulation is unclear. Aims To investigate the effects of chronic NPS administration on AD-related sleep disturbances beyond its acute wake-promoting effects. Methods NPSR expression was examined in the hypothalamus and hippocampus of APPswe/PS1dE9 (APP/PS1) mice, a double-transgenic mouse model of AD. Mice received intracerebroventricular NPS (1 nmol/day) for 14 days. Sleep–wake states were classified as wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. Sleep architecture and amyloid-β (Aβ)-related pathology were assessed in mice. Cell-associated Aβ levels, extracellular signal-regulated kinase (ERK) phosphorylation, and autophagy-related proteins were examined in BV2 cells. Sleep responses to subsequent intracerebroventricular Aβ₁–₄₂ administration were examined in NPS-treated APP/PS1 mice. Results APP/PS1 mice had lower NPSR protein levels in the hypothalamus and hippocampus than wild-type (WT) controls. Compared with saline-treated APP/PS1 mice, NPS-treated mice showed increased NREM sleep, reduced wakefulness, and lower Aβ-related pathology. Changes in sleep amounts were most evident during the light phase. Subsequent Aβ₁–₄₂ administration increased wakefulness and reduced NREM sleep mainly during the dark phase. It also shortened NREM episodes during the light phase. In BV2 cells, NPS altered cell-associated Aβ levels and increased ERK phosphorylation. NPS treatment was also associated with higher LC3B-II and lower p62 levels. SCH772984 attenuated the NPS-associated changes in autophagy-related proteins and cell-associated Aβ. Conclusion Chronic NPS administration improved sleep architecture and reduced Aβ-related pathology in APP/PS1 mice. The BV2 findings suggest possible involvement of ERK signaling and autophagy-related processes in cellular Aβ handling.