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Lemborexant ameliorates tau-mediated sleep loss and neurodegeneration in males in a mouse model of tauopathy

Nature Neuroscience (2025)Cite this article

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Abstract

Sleep disturbances are associated with the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and primary tauopathies. Here we demonstrate that administration of the dual orexin receptor antagonist lemborexant in the P301S/E4 mouse model of tauopathy improves tau-associated impairments in sleep–wake behavior. It also protects against chronic reactive microgliosis and brain atrophy in male P301S/E4 mice by preventing abnormal phosphorylation of tau. These neuroprotective effects in males were not observed after administration of the nonorexinergic drug zolpidem that similarly promoted nonrapid eye movement sleep. Furthermore, both genetic ablation of orexin receptor 2 and lemborexant treatment reduced wakefulness and decreased seeding and spreading of phosphorylated tau in the brain of wild-type mice. These findings raise the therapeutic potential of targeting sleep by orexin receptor antagonism to prevent abnormal tau phosphorylation and limit tau-induced damage.

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Fig. 1: Zolpidem and lemborexant treatment increase NREM sleep in male P301S/E4 mice.
Fig. 2: OXR antagonism is partially neuroprotective in P301S/E4 mice.
Fig. 3: Blocking OXR signaling alters microglial reactivity in male P301S/E4 mice.
Fig. 4: Lemborexant alters synaptic receptor and GPCR ligand binding activity pathways.
Fig. 5: Lemborexant treatment reduces hyperphosphorylated pathological tau in male P301S/E4 mice.
Fig. 6: OXR antagonism reduces cAMP/PKA-mediated phosphorylation of tau in P301S/E4 male mice.
Fig. 7: Pharmacological or genetic lack of OXR signaling decreases tau seeding and cAMP/PKA-mediated phosphorylation of tau.

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Data availability

Numerical source data files are available as supplementary data files. RNA-seq data are publicly available from the Gene Expression Omnibus under accession code GSE283736. Source data are provided with this paper.

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Acknowledgements

We thank Eisai for providing lemborexant. We would like to thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. This study was supported by the National Institutes of Health (grants P01NS074969, RF1NS090934 and RF1AG061776 to D.M.H.), the Freedom Together Foundation (to D.M.H.), the Alzheimer’s Association (AARF-21-850865 to S.P.) and the COBRAS Feldman Fellowship (to S.P.).

Author information

Authors and Affiliations

  1. Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA

    Samira Parhizkar, Xin Bao, Wei Chen, Nicholas Rensing, Yun Chen, Michal Kipnis, Sihui Song, Grace Gent, Melissa Manis, Choonghee Lee, Javier Remolina Serrano, Megan E. Bosch, Emily Franke, Carla M. Yuede, Eric C. Landsness, Michael Wong & David M. Holtzman

  2. Genome Technology Access Center, Washington University School of Medicine, St. Louis, MO, USA

    Eric Tycksen

  3. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA

    Carla M. Yuede

  4. Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA

    Carla M. Yuede

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Contributions

S.P. and D.M.H. designed the study. S.P. and X.B. orally gavaged the mice and collected and analyzed the Piezosleep data. S.P., X.B., C.L., G.G. and J.R.S. perfused and collected samples. N.R., W.C., S.P., E.C.L. and M.W. collected and analyzed all EEG/EMG data. Y.C. and S.S. performed the AD-tau extract preparation and intrahippocampal injections. E.T. performed the RNA-sequencing analysis. S.P., X.B., G.G., M.K. and E.F. performed and analyzed the immunohistochemistry, imaging, RNA and protein extraction, qPCR, immunoblotting and ELISA experiments. M.M. and X.B. performed and analyzed the NFL SIMOA data. S.P., X.B., G.G. and M.E.B. maintained the mouse colony. C.M.Y. collected and analyzed all behavioral experiments. S.P. wrote the draft. D.M.H. reviewed and edited the paper. All authors discussed the results and commented on the paper.

Corresponding author

Correspondence to David M. Holtzman.

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Competing interests

D.M.H. is an inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies; cofounded and is on the scientific advisory board of C2N Diagnostics; is on the scientific advisory board of Denali, Genentech, Cajal Neuroscience and Switch Therapeutics and consults for Pfizer and Roche. The other authors declare no competing interests.

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Nature Neuroscience thanks Li Gan, Tara Spires-Jones and Sigrid Veasey for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Lemborexant influences sleep–wake behavior but does not influence reactive microglia or astroglia in non-tau transgenic E4 mice.

a, EEG analyses of percentage time spent in NREM sleep (nE4 = 10 mice/group, nP301S/E4 = 8 mice/group, two-way ANOVA, Fisher’s LSD test), REM sleep (nE4 = 10 mice per group, nP301S/E4 = 8 mice/group, two-way ANOVA, Fisher’s LSD test) and awake (nE4 = 10 mice/group, nP301S/E4 = 8 mice/group; two-way ANOVA and Fisher’s LSD test) in Veh- and Lem-treated E4 and P301S/E4 male mice at ZT13. b, EEG analyses of percentage sleep in the first 4 h after gavage (n = 4 mice/group; two-tailed t test) as well as percentage time spent in NREM sleep (n = 4 mice/group; one-way ANOVA and Dunnett’s post hoc test), REM sleep (n = 4 mice/group; Kruskal–Wallis test) and awake (n = 4 mice/group; one-way ANOVA and Dunnett’s post hoc test) in female P301S/E4 mice. c, Representative confocal images of Iba1 (green), Cd68 (red) and Tmem119 (yellow) stained reactive microglia in Ent/Pcx of Veh or Lem ZT13 treated E4 male mice. Scale bar, 20 μm. d–g, Quantifications as labeled (Iba1: nVeh = 15, nLem ZT13 = 16, two-tailed t test; Cd68: nVeh = 14, nLem ZT13 = 18, two-tailed t test, p = 0.9721; Tmem119: nVeh = 17, nLem ZT13 = 20, two-tailed t test; Gfap: nVeh = 16, nLem ZT13 = 17, two-tailed t test). For detailed statistical information, see Supplementary Table 1. Data represent mean ± s.e.m. of biological replicates; *P < 0.05, *P < 0.01, ***P< 0.001, and ****P<0.0001.

Source data

Extended Data Fig. 2 Behavioral assessment across different treatment groups in P301S/E4 mice.

a, Percentage freezing quantified during tone–shock/pairing (males: nVeh = 19, nZol ZT13 = 14, nLem ZT3 = 12, nLem ZT13 = 13, two-way ANOVA, Dunnett’s post hoc test; females: nVeh = 17, nLem ZT3 = 15, nLem ZT13 = 9, two-way ANOVA, Dunnett’s post hoc test); b, contextual conditioning (males: nVeh = 19, nZol ZT13 = 14, nLem ZT3 = 12, nLem ZT13 = 13, two-way ANOVA, Dunnett’s post hoc test; females: nVeh = 17, nLem ZT3 = 15, nLem ZT13 = 9, two-way ANOVA, Dunnett’s post hoc test); c, auditory cue conditioning (males: nVeh = 19, nZol ZT13 = 14, nLem ZT3 = 9, nLem ZT13 = 13, two-way ANOVA, Dunnett’s post hoc test; females: nVeh = 17, nLem ZT3 = 15, nLem ZT13 = 9, two-way ANOVA, Dunnett’s post hoc test). d, Percentage alternation rate quantified in Y-maze alternation test (males: nVeh = 19, nZol ZT13 = 14, nLem ZT3 = 12, nLem ZT13 = 13, one-way ANOVA, Dunnett’s post hoc test; females: nVeh = 17, nLem ZT3 = 14, nLem ZT13 = 9, one-way ANOVA). For detailed statistical information, see Supplementary Table 1. Data represent mean ± s.e.m. in biological replicates. *P < 0.05, and ** P< 0.01.

Source data

Extended Data Fig. 3 Orexin receptor antagonism does not influence cAMP/PKA-mediated phosphorylation of tau in P301S/E4 female mice.

a, DAG (nVeh = 15, nLem ZT3 = 15, nLem ZT13 = 12; Kruskal–Wallis and Dunn’s post hoc test); b, cAMP (nVeh = 14, nLem ZT3 = 16, nLem ZT13 = 16; one-way ANOVA and Dunnett’s post hoc test) ELISAs of RIPA-soluble Ent/Pcx extracts. c, Immunoblots of RIPA-soluble Ent/Pcx brain extracts from Veh- and Lem-treated female P301S/E4 mice (n = 3 mice/group). d–h, Quantification of the western blot intensity of protein kinases and cell signaling proteins (for d, e and g—nVeh = 9, nLem ZT3 = 9, nLem ZT13 = 8; for f—nVeh = 9, nLem ZT3 = 9, nLem ZT13 = 7; for h—nVeh = 9, nLem ZT3 = 8, nLem ZT13 = 8). All proteins were first normalized to Gapdh, and the ratio of phosphorylated to their corresponding unphosphorylated form was then calculated. PHF1 was normalized to Gapdh. (d—Kruskal-Wallis test and Dunn’s post hoc test; e—one-way ANOVA, Dunnett’s post hoc test; f—one-way ANOVA, Dunnett’s post hoc test; g—Kruskal–Wallis test and Dunn’s post hoc test; h—one-way ANOVA, Dunnett’s post hoc test). For detailed statistical information, see Supplementary Table 1. Data represent mean ± s.e.m. of biological replicates. *P< 0.05, and ****P < 0.0001.

Source data

Extended Data Fig. 4 Gene expression levels of orexin-mediated GPCR signaling molecules.

a–i, Gene expression levels of orexin receptors and downstream effectors in naïve male P301S/E4 mice compared at ZT3 and ZT13 (n = 6 mice/group; a–d, f–i, two-tailed t test; e—Mann–Whitney test), and (j–r) Veh- and Lem-treated male mice (j—nVeh = 9, nLem ZT3 = 7, nLem ZT13 = 7; one-way ANOVA and Dunnett’s post hoc test; k—nVeh = 9, nLem ZT3 = 7, nLem ZT13 = 7; Kruskal–Wallis test and Dunn’s post hoc test; l—nVeh = 8, nLem ZT3 = 7, nLem ZT13 = 7; Kruskal–Wallis test and Dunn’s post hoc test; m—nVeh = 8, nLem ZT3 = 7, nLem ZT13 = 7; one-way ANOVA and Dunnett’s post hoc test; n—nVeh = 9, nLem ZT3 = 7, nLem ZT13 = 7; Kruskal–Wallis test and Dunn’s post hoc test; o—nVeh = 9, nLem ZT3 = 7, nLem ZT13 = 7; one-way ANOVA and Dunnett’s post hoc test; p—nVeh = 9, nLem ZT3 = 7, nLem ZT13 = 7; one-way ANOVA, p = 0.5522; Dunnett’s post hoc test; q—nVeh = 9, nLem ZT3 = 7, nLem ZT13 = 7; Kruskal–Wallis and Dunn’s post hoc test; r—nVeh = 9, nLem ZT3 = 7, nLem ZT13 = 7; one-way ANOVA and Dunnett’s post hoc test). For detailed statistical information, see Supplementary Table 1. Data represent mean ± s.e.m. of biological replicates.

Source data

Extended Data Fig. 5 Pharmacological or genetic lack of orexin receptor signaling alters sleep–wake behavior and decreases tau propagation.

a, Sleep–wake behavior quantified by percentage sleep (two-way ANOVA and Sidak’s post hoc test), sleep bout lengths (two-way ANOVA and Sidak’s post hoc test) and wake bout lengths (two-way ANOVA and Sidak’s post hoc test) during the light and dark phase at 7.5 M (nOXR2-WT = 8, nOXR2-WT Lem = 7, nOXR2-KO = 8) male mice. b, Sleep–wake behavior quantified by percentage sleep (two-way ANOVA and Sidak’s post hoc test), sleep bout lengths (two-way ANOVA and Sidak’s post hoc test) and wake bout lengths (two-way ANOVA and Sidak’s post hoc test) during the light and dark phase at 9.5 M (nOXR2-WT = 8, nOXR2-WT Lem = 7, nOXR2-KO = 8) in male mice. c, Percentage sleep in dark phase compared between mice at 7.5 M and 9.5 M (both timepoints: nOXR2-WT = 8, nOXR2-WT Lem = 7, nOXR2-KO = 8; two-way ANOVA and Bonferroni’s post hoc test). d, Wake bout lengths compared between mice at 7.5 M and 9.5 M during dark phase (both timepoints: nOXR2-WT = 8, nOXR2-WT Lem = 7, nOXR2-KO = 8; two-way ANOVA and Bonferroni’s post hoc test). e, Representative images of PG5-stained anterior (ant; top) and posterior (pos; bottom) Hpc. Scale bar, 500 μm. f, Percentage PG5-covered dentate gyrus quantified anterior (nOXR2-WT = 8, nOXR2-WT Lem = 7, nOXR2-KO = 8 male mice; one-way ANOVA and Dunnett’s post hoc test); g, posterior to the seeding site (one-way ANOVA and Dunnett’s post hoc test). h, Representative images of AT8-stained anterior and posterior Hpc. Scale bar, 500 μm. i, Percentage AT8-covered dentate gyrus quantified anterior (nOXR2-WT = 8, nOXR2-WT Lem = 7, nOXR2-KO = 8 male mice; one-way ANOVA and Dunnett’s post hoc test); j, posterior to the seeding site (Kruskal–Wallis test and Dunn’s post hoc test). For detailed statistical information, see Supplementary Table 1. Data represent mean ± s.e.m. in biological replicates. *P< 0.05, **P< 0.01, ***P<0.001, and ****P < 0.0001.

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Supplementary Table 1

Detailed statistical data for Figs. 1–7 and Extended Data Figs. 1–5.

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Parhizkar, S., Bao, X., Chen, W. et al. Lemborexant ameliorates tau-mediated sleep loss and neurodegeneration in males in a mouse model of tauopathy. Nat Neurosci (2025). https://doi.org/10.1038/s41593-025-01966-7

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