Chronic neuropeptide S treatment improves sleep architecture and reduces Aβ-related pathology in APP/PS1 mice
- 1Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University
- 2Jiangnan University Hospital, Jiangnan University
Abstract
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.
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BibTeX
@article{zhao2026chronic,
title = {{Chronic neuropeptide S treatment improves sleep architecture and reduces Aβ-related pathology in APP/PS1 mice}},
author = {Yiru Zhao and Miaomiao Liu and Yanjun Zhou and Meng Cui and Nianshan Cai and Haiyi Wang and Guangming Liu and Hongxu Sun and Xiangpan Kong and Peng Zhao},
journal = {Frontiers in Neurology},
year = {2026},
month = oct,
doi = {10.3389/fneur.2026.1825666},
url = {https://www.frontiersin.org/articles/10.3389/fneur.2026.1825666/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Chronic neuropeptide S treatment improves sleep architecture and reduces Aβ-related pathology in APP/PS1 mice
AU - Yiru Zhao
AU - Miaomiao Liu
AU - Yanjun Zhou
AU - Meng Cui
AU - Nianshan Cai
AU - Haiyi Wang
AU - Guangming Liu
AU - Hongxu Sun
AU - Xiangpan Kong
AU - Peng Zhao
PY - 2026
DA - 2026/10/26
JO - Frontiers in Neurology
DO - 10.3389/fneur.2026.1825666
UR - https://www.frontiersin.org/articles/10.3389/fneur.2026.1825666/full
AB - 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.
SN - 1664-2295
ER -