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Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer’s disease
Open accessAbstract
Age-related aggregation of amyloid-β (Aβ) is an upstream pathological event in Alzheimer’s disease (AD) pathogenesis, and it disrupts the sleep–wake cycle. The amount of sleep declines with aging and to a greater extent in AD. Poor sleep quality and insufficient amounts of sleep have been noted in humans with preclinical evidence of AD. However, how the amount and quality of sleep affects Aβ aggregation is not yet well understood. Orexins (hypocretins) initiate and maintain wakefulness, and loss of orexin-producing neurons causes narcolepsy. We tried to determine whether orexin release or secondary changes in sleep via orexin modulation affect Aβ pathology. Amyloid precursor protein (APP)/Presenilin 1 (PS1) transgenic mice, in which the orexin gene is knocked out, showed a marked decrease in the amount of Aβ pathology in the brain with an increase in sleep time. Focal overexpression of orexin in the hippocampus in APP/PS1 mice did not alter the total amount of sleep/wakefulness and the amount of Aβ pathology. In contrast, sleep deprivation or increasing wakefulness by rescue of orexinergic neurons in APP/PS1 mice lacking orexin increased the amount of Aβ pathology in the brain. Collectively, modulation of orexin and its effects on sleep appear to modulate Aβ pathology in the brain.
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In transgenic mouse models of Alzheimer's disease, SWS restriction accelerates activity-dependent amyloidβ aggregation, whereas SWS enhancement delays aggregation.
“Recent studies in transgenic mouse models of Alzheimer's disease (AD) reveal that SWS restriction accelerates activity-dependent amyloid𝛃 aggregation, whereas SWS enhancement delays aggregation [5].”
From Long-Term Trazodone Use and Cognition: A Potential Therapeutic Role for Slow-Wave Sleep Enhancers (2019) · cites this paper as [5]
The Results and Discussion section ('Sleep deprivation induced Aβ pathology in OR−/− mice'; page unavailable) reports increased Aβ plaque pathology after sleep deprivation, while increased sleep time with orexin deficiency was associated with reduced pathology. The study does not specifically test restriction or enhancement of slow-wave sleep (SWS), and it presents the neuronal-activity mechanism as supported but not established to the exclusion of other mechanisms. (LLM, conf=0.86)
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Cites
A default mode of brain function
Raichle, M. E., MacLeod, A. M., Snyder, A. Z., Powers, W. J., Gusnard, D. A., & Shulman, G. L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.2.676 · Cited by 12,190
Sperling, R. A., Aisen, P. S., Beckett, L. A., Bennett, D. A., Craft, S., Fagan, A. M., Iwatsubo, T., Jack, C. R., Kaye, J., Montine, T. J., et al. (2011) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.03.003 · Cited by 7,155
Sleep Drives Metabolite Clearance from the Adult Brain
Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., O’Donnell, J., Christensen, D. J., Nicholson, C., Iliff, J. J., et al. (2013) · Science · doi:10.1126/science.1241224 · Cited by 5,411
The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity
de Lecea, L., Kilduff, T. S., Peyron, C., Gao, X.-B., Foye, P. E., Danielson, P. E., Fukuhara, C., Battenberg, E. L. F., Gautvik, V. T., Bartlett, F. S., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.1.322 · Cited by 3,878
Aβ42‐driven cerebral amyloidosis in transgenic mice reveals early and robust pathology
Radde, R., Bolmont, T., Kaeser, S. A., Coomaraswamy, J., Lindau, D., Stoltze, L., Calhoun, M. E., Jäggi, F., Wolburg, H., Gengler, S., et al. (2006) · The EMBO Reports · doi:10.1038/sj.embor.7400784 · Cited by 986
Vyazovskiy, V. V., Olcese, U., Hanlon, E. C., Nir, Y., Cirelli, C., & Tononi, G. (2011) · Nature · doi:10.1038/nature10009 · Cited by 865
Roh, J. H., Huang, Y., Bero, A. W., Kasten, T., Stewart, F. R., Bateman, R. J., & Holtzman, D. M. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004291 · Cited by 563
Self-citationOoms, S., Overeem, S., Besse, K., Rikkert, M. O., Verbeek, M., & Claassen, J. A. H. R. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2014.1173 · Cited by 438
Spatial correlation between brain aerobic glycolysis and amyloid-β (Aβ) deposition
Vlassenko, A. G., Vaishnavi, S. N., Couture, L., Sacco, D., Shannon, B. J., Mach, R. H., Morris, J. C., Raichle, M. E., & Mintun, M. A. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1010461107 · Cited by 404
Cirrito, J. R., May, P. C., O'Dell, M. A., Taylor, J. W., Parsadanian, M., Cramer, J. W., Audia, J. E., Nissen, J. S., Bales, K. R., Paul, S. M., et al. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-26-08844.2003 · Cited by 394
Self-citationKim, J., Castellano, J. M., Jiang, H., Basak, J. M., Parsadanian, M., Pham, V., Mason, S. M., Paul, S. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.11.013 · Cited by 274
Self-citationKoenigsknecht-Talboo, J., Meyer-Luehmann, M., Parsadanian, M., Garcia-Alloza, M., Finn, M. B., Hyman, B. T., Bacskai, B. J., & Holtzman, D. M. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4147-08.2008 · Cited by 149
Flagged first, then by citations
Research works printed but not linked: 16
- Bero, 2011, Neuronal activity regulates the regional vulnerability to amyloid-β deposition, Nat. Neurosci., 14, 750, 10.1038/nn.2801 · DOI · Paper page
- Carter, 2010, Tuning arousal with optogenetic modulation of locus coeruleus neurons, Nat. Neurosci., 13, 1526, 10.1038/nn.2682 · DOI · Paper page
- Chemelli, 1999, Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation, Cell., 98, 437, 10.1016/S0092-8674(00)81973-X · DOI · Paper page
- Cirrito, 2008, Endocytosis is required for synaptic activity-dependent release of amyloid-β in vivo, Neuron., 58, 42, 10.1016/j.neuron.2008.02.003 · DOI · Paper page
- Holtzman, 2011, Mapping the road forward in Alzheimer’s disease, Sci. Transl. Med., 3, 114ps48, 10.1126/scitranslmed.3003529 · DOI
- Jankowsky, 2004, Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase, Hum. Mol. Genet., 13, 159, 10.1093/hmg/ddh019 · DOI · Paper page
- Ju, 2013, Sleep evaluation by actigraphy for patients with Alzheimer disease—reply, JAMA Neurol., 70, 1074, 10.1001/jamaneurol.2013.3490 · DOI
- Ju, 2014, Sleep and Alzheimer disease pathology—a bidirectional relationship, Nat Rev Neurol., 10, 115, 10.1038/nrneurol.2013.269 · DOI · Paper page
- Kamenetz, 2003, APP processing and synaptic function, Neuron., 37, 925, 10.1016/S0896-6273(03)00124-7 · DOI · Paper page
- Kang, 2009, Amyloid-β dynamics are regulated by orexin and the sleep-wake cycle, Science., 326, 1005, 10.1126/science.1180962 · DOI · Paper page
- Matsuki, 2009, Selective loss of GABAB receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture, Proc. Natl. Acad. Sci. USA., 106, 4459, 10.1073/pnas.0811126106 · DOI
- Nir, 2011, Regional slow waves and spindles in human sleep, Neuron., 70, 153, 10.1016/j.neuron.2011.02.043 · DOI · Paper page
- Spira, 2013, Self-reported sleep and β-amyloid deposition in community-dwelling older adults, JAMA Neurol., 70, 1537
- Vyazovskiy, 2009, Cortical firing and sleep homeostasis, Neuron., 63, 865, 10.1016/j.neuron.2009.08.024 · DOI · Paper page
- Yamada, 2014, Neuronal activity regulates extracellular tau in vivo, J. Exp. Med., 211, 387, 10.1084/jem.20131685 · DOI
- Yan, 2009, Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice, J. Neurosci., 29, 10706, 10.1523/JNEUROSCI.2637-09.2009 · DOI · Paper page
Cited by
Sorted by citations
Mechanisms linking circadian clocks, sleep, and neurodegeneration
Musiek, E. S., & Holtzman, D. M. (2016) · Science · doi:10.1126/science.aah4968 · Cited by 878
Self-citationSlow wave sleep disruption increases cerebrospinal fluid amyloid-β levels
Ju, Y.-E. S., Ooms, S. J., Sutphen, C., Macauley, S. L., Zangrilli, M. A., Jerome, G., Fagan, A. M., Mignot, E., Zempel, J. M., Claassen, J. A. H. R., et al. (2017) · Brain · doi:10.1093/brain/awx148 · Cited by 604
Self-citationNeuropsychiatric signs and symptoms of Alzheimer's disease: New treatment paradigms
Lanctôt, K. L., Amatniek, J., Ancoli‐Israel, S., Arnold, S. E., Ballard, C., Cohen‐Mansfield, J., Ismail, Z., Lyketsos, C., Miller, D. S., Musiek, E., et al. (2017) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2017.07.001 · Cited by 395
Mechanisms of secretion and spreading of pathological tau protein
Brunello, C. A., Merezhko, M., Uronen, R.-L., & Huttunen, H. J. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03349-1 · Cited by 304
The discovery of suvorexant, the first orexin receptor drug for insomnia
Coleman, P. J., Gotter, A. L., Herring, W. J., Winrow, C. J., & Renger, J. J. (2017) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010716-104837 · Cited by 128
Long-Term Trazodone Use and Cognition: A Potential Therapeutic Role for Slow-Wave Sleep Enhancers
La, A. L., Walsh, C. M., Neylan, T. C., Vossel, K. A., Yaffe, K., Krystal, A. D., Miller, B. L., & Karageorgiou, E. (2019) · Journal of Alzheimer's Disease · doi:10.3233/jad-181145 · Cited by 83
Central and peripheral circadian clocks and their role in Alzheimer's disease
Chauhan, R., Chen, K.-F., Kent, B. A., & Crowther, D. C. (2017) · Disease Models & Mechanisms · doi:10.1242/dmm.030627 · Cited by 58
“Orexin knockout mice sleep more than controls (Chemelli et al., 1999), and when crossed with APP/ PSEN1 mice, they exhibit a marked reduction in Aβ plaque deposition (Roh et al., 2014).”
Kim, E., Nohara, K., Wirianto, M., Escobedo, G., Lim, J. Y., Morales, R., Yoo, S.-H., & Chen, Z. (2021) · Biomolecules · doi:10.3390/biom11071004 · Cited by 51
Daulatzai, M. A. (2015) · Neurotoxicity Research · doi:10.1007/s12640-015-9528-x · Cited by 12
Mitochondrial Function and Neurodegenerative Diseases
Wilkins, H. M., Weidling, I., Koppel, S., Wang, X., von Schulze, A., & Swerdlow, R. H. (2018) · The Molecular and Cellular Basis of Neurodegenerative Diseases · doi:10.1016/b978-0-12-811304-2.00013-4 · Cited by 2
Metadata
- Authors
- Roh, J. H., Jiang, H., Finn, M. B., Stewart, F. R., Mahan, T. E., Cirrito, J. R., Heda, A., Snider, B. J., Li, M., Yanagisawa, M., de Lecea, L., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- The University of Texas Southwestern Medical Center (US)
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305 6
- Corresponding author
- Holtzman, David M.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2014-11-24
- Volume
- 211
- Issue
- 13
- Pages
- 2487-2496
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC4267230
- OpenAlex
- W2113732004
- Cited by
- 237
- References
- 12
- Citations by year
- 2026: 10 · 2025: 26 · 2024: 16 · 2023: 24 · 2022: 20 · 2021: 22 · 2020: 25 · 2019: 20 · 2018: 18 · 2017: 27 · 2016: 18 · 2015: 10 · 2014: 1
- FWCI
- 8.58
- Type
- journal article
- Language
- en
- Update notices
- correction (2014-12-22)
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-sa)
- Funders
- Ellison Medical Foundation
- Eli Lilly and Company
- Cure Alzheimer's Fund (P01NS074969)
- Hope Center for Neurological Disorders
- National Research Foundation
- Ministry of Science, ICT and Future Planning (2013R1A1A1012925, 2008-0062286)
- Korea Institute of Science and Technology
- National Research Foundation of Korea (2008-0062286)
- Medical Research Council (2008-0062286)
- Japan Society for the Promotion of Science (26220207)
- National Institute on Aging (R01AG047671)
- National Institute of Neurological Disorders and Stroke (P30NS057105, R01NS090934, P01NS074969)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- orexin, Alzheimer's disease, amyloid-beta aggregation, sleep-wake cycle, sleep deprivation, wakefulness, APP/PS1 mice, hippocampus, orexinergic neurons, narcolepsy
- MeSH terms
- Orexins, Alzheimer Disease, Animals, Chronic Disease, Circadian Rhythm, Genetic Vectors, Humans, Neuropeptides, Promoter Regions, Genetic, Sleep, Sleep Deprivation, Wakefulness, Amyloid beta-Peptides, Mice, Knockout, Intracellular Signaling Peptides and Proteins, Presenilin-1
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