OSCR

Dual orexin receptor antagonism with lemborexant enhances microglial clearance of β-amyloid in mice.

Overview

Authors: Ashish Sharma1, Emiko Segawa2, Xiaoying Chen3, Sohui Park1, Shoutang Wang4,5, Riley E Irmen6, Nicholas J Constantino6, Chanung Wang1, Michael F Kanan1, Marco Colonna4, Shannon L Macauley6, Jocelyn Y Cheng7, Ken Hatanaka2, Margaret Moline7, Erik S Musiek1
ORCID iDs: Ashish Sharma, Xiaoying Chen, Sohui Park, Michael F Kanan, Erik S Musiek
  1. Department of Neurology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO USA
  2. Eisai Co., Ltd., Tsukuba, Ibaraki Japan
  3. Laboratory of System Neuroimmunology, Institute for Immunology at Tsinghua, IDG/McGovern Institute for Brain Research at Tsinghua, School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing, China
  4. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO USA
  5. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong, China
  6. Department of Physiology, Department of Neuroscience, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY USA
  7. Eisai Inc., Nutley, NJ USA
Institutions: Washington University in St. Louis (United States); Hope Center for Neurological Disorders (United States); Eisai (Japan) (Japan); Tsinghua University (China); University of Hong Kong (Hong Kong SAR China); University of Kentucky (United States); Eisai (United States) (United States)
Journal: Molecular neurodegeneration, volume 21, issue 1, article 28
Dates: received 29 September 2025; accepted 8 May 2026; published online 22 May 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s13024-026-00948-y · PMID 42174655 · PMCID PMC13214429 · OpenAlex W7162128489
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), histology / microscopy (modality), mouse (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions, Machine learning, Preprocessing, Physiology & signal measures
Keywords: Alzheimer’s disease, Amyloid plaques, Sleep, Orexin, Microglia
MeSH: Alzheimer Disease*, Amyloid beta-Peptides*, Microglia*, Orexin Receptor Antagonists*, Pyridines*, Pyrimidines*, Animals, Brain, Mice, Mice, Transgenic, Orexin Receptors, Plaque, Amyloid, Sleep (* major topic)
Topic: Sleep and Wakefulness Research (Cognitive Neuroscience, Neuroscience), according to OpenAlex
Funding: NCI NIH HHS (P30 CA091842)
Citations: not cited yet (Europe PMC); 90 references in the paper

Abstract

Background: Sleep disturbances elevate brain amyloid-beta (Aβ) levels and represent a modifiable risk factor for Alzheimer’s disease (AD). The orexin/hypocretin system regulates sleep–wake behavior and has emerged as a therapeutic target in AD; however, the effects of FDA-approved dual orexin receptor antagonists (DORAs) on amyloid pathology remain unclear. We compared lemborexant, an FDA-approved DORA, to doxepin, an antihistaminergic sleep medication, on amyloid pathology and microglial responses in PSAPP mice.

Methods: PSAPP mice received lemborexant (10 or 30 mg/kg/day), doxepin (35 mg/kg/day), or vehicle for 6 weeks beginning prior to plaque onset or 4 weeks after established pathology. Sleep was assessed by piezoelectric monitoring and EEG/EMG polysomnography. Amyloid pathology and microglial responses were quantified by immunohistochemistry, confocal microscopy, and single-cell RNA sequencing. Microglial depletion was induced with the CSF1R inhibitor PLX3397.

Results: Lemborexant enhanced sleep quality with less active-phase sedation than doxepin. Both drugs reduced initial diffuse plaque deposition, but only lemborexant prevented fibrillar plaque accumulation in young mice and slowed plaque growth in older mice. Lemborexant increased peri-plaque microglial CD68 expression and enhanced Aβ phagocytosis in vivo. Single-cell transcriptomics revealed a shift toward activated, DAM-like microglial states with upregulation of phagocytic genes without broad inflammatory induction. Microglial depletion abolished lemborexant’s anti-amyloid effects.

Conclusions: Lemborexant mitigates amyloid pathology by augmenting microglial phagocytic function, positioning DORAs as promising therapeutics that couple sleep promotion with beneficial microglial modulation.

Supplementary information: The online version contains supplementary material available at 10.1186/s13024-026-00948-y.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

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Data

Datasets cited

Data availability

The scRNAseq dataset is freely available on the NIH GEO website under accession number GSE312840 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE312840).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 15 authors, 5 keywords, 13 MeSH terms, 1 funder, 90 references.

Cite

This paper

Sharma, A., Segawa, E., Chen, X., Park, S., Wang, S., Irmen, R. E., Constantino, N. J., Wang, C., Kanan, M. F., Colonna, M., Macauley, S. L., Cheng, J. Y., Hatanaka, K., Moline, M., & Musiek, E. S. (2026). Dual orexin receptor antagonism with lemborexant enhances microglial clearance of β-amyloid in mice. Molecular neurodegeneration, 21(1), 28. https://doi.org/10.1186/s13024-026-00948-y

BibTeX

@article{sharma2026dual,
author = {Sharma, Ashish and Segawa, Emiko and Chen, Xiaoying and Park, Sohui and Wang, Shoutang and Irmen, Riley E and Constantino, Nicholas J and Wang, Chanung and Kanan, Michael F and Colonna, Marco and Macauley, Shannon L and Cheng, Jocelyn Y and Hatanaka, Ken and Moline, Margaret and Musiek, Erik S},
title = {{Dual orexin receptor antagonism with lemborexant enhances microglial clearance of β-amyloid in mice}},
journal = {Molecular neurodegeneration},
year = {2026},
month = may,
volume = {21},
number = {1},
pages = {28},
publisher = {BMC},
issn = {1750-1326},
doi = {10.1186/s13024-026-00948-y},
url = {https://doi.org/10.1186/s13024-026-00948-y},
pmid = {42174655},
pmcid = {PMC13214429}
}

RIS

TY - JOUR
AU - Sharma, Ashish
AU - Segawa, Emiko
AU - Chen, Xiaoying
AU - Park, Sohui
AU - Wang, Shoutang
AU - Irmen, Riley E
AU - Constantino, Nicholas J
AU - Wang, Chanung
AU - Kanan, Michael F
AU - Colonna, Marco
AU - Macauley, Shannon L
AU - Cheng, Jocelyn Y
AU - Hatanaka, Ken
AU - Moline, Margaret
AU - Musiek, Erik S
TI - Dual orexin receptor antagonism with lemborexant enhances microglial clearance of β-amyloid in mice
T2 - Molecular neurodegeneration
J2 - Mol Neurodegener
PY - 2026
DA - 2026/05/22
VL - 21
IS - 1
SP - 28
SN - 1750-1326
PB - BMC
DO - 10.1186/s13024-026-00948-y
UR - https://doi.org/10.1186/s13024-026-00948-y
LA - en
ER -

CSL-JSON

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