Introduction: Sleep disruption is a characteristic of Alzheimer's disease (AD) that may exacerbate disease progression. This study tested whether a dual orexin receptor antagonist (DORA) would enhance sleep and attenuate neuropathology, neuroinflammation, and cognitive deficits in an AD-relevant mouse model, 5XFAD.

Methods: Wild-type (C57Bl6/SJL) and 5XFAD mice received chronic treatment with vehicle or DORA-22. Piezoelectric recordings monitored sleep and spatial memory was assessed via spontaneous Y-maze alternations. Aβ plaques, Aβ levels, and neuroinflammatory markers were measured by immunohistochemistry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction, respectively.

Results: In 5XFAD mice, DORA-22 significantly increased light-phase sleep without reducing Aβ levels, plaque density, or neuroinflammation. Effects of DORA-22 on cognitive deficits could not be determined because the 5XFAD mice did not exhibit deficits.

Discussion: These findings suggest that DORAs may improve sleep in AD patients. Further investigations should optimize the dose and duration of DORA-22 treatment and explore additional AD-relevant animal models and cognitive tests.

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Notes/Citation Information

Published in Alzheimer's & Dementia: Translational Research & Clinical Interventions, v. 5, p. 70-80.

© 2019 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).

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Funding Information

This research was supported by a contract from Merck (MIS #201607071502 [M.J.D. and B.F.O.]), pilot funds from National Institutes of Health (NIH) grant NIH-5P30AG02838 (L. Van Eldik, PI of grant; M.J.D. and A.D.B., MPIs of pilot study), NIH R00 AG044445 (A.D.B.), and pilot funds from the University of Kentucky, Department of Neuroscience (M.J.D. and A.D.B.).

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Supplementary data related to this article can be found at https://doi.org/10.1016/j.trci.2019.01.003.

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Supplementary 1

mmc2.pdf (954 kB)
Supplementary 2