Glial cytokine modulation improves sleep and circadian disruption in female SAA knock-in mice of Alzheimer’s-related pathology

Authors

• Teresa Macheda, University of KentuckyFollow
• Margaret R. Hawkins, University of Kentucky
• Carrie E. Johnson, University of Kentucky
• Madison G. Lapid, University of Kentucky
• Haleigh R. Whitlock, University of Kentucky
• Savannah M. Shepard, University of Kentucky
• MaKayla F. Cox, University of Kentucky
• Kelly N. Roberts, University of KentuckyFollow
• Leke Bytyqi, University of Kentucky
• Heather M. Hash, University of Kentucky
• Omar A. Abou El-Ezz, University of Kentucky
• Mohammed Abou El-Ezz, University of Kentucky
• Katharina Kohler, University of KentuckyFollow
• Sridhar Sunderam, University of KentuckyFollow
• Bruce F. O'Hara, University of KentuckyFollow
• Linda J. Van Eldik, University of KentuckyFollow
• Michael Paul Murphy, University of KentuckyFollow
• Marilyn J. Duncan, University of KentuckyFollow
• Adam D. Bachstetter, University of KentuckyFollow

Abstract

Introduction: Sleep and circadian disturbances are early Alzheimer's disease (AD) features, yet mechanisms linking amyloid pathology, neuroinflammation, and sex differences remain unclear.

Methods: We longitudinally assessed sleep, circadian rhythms, and cognition in female and male hAPP^SAA knock-in and control mice from 2 to 19 months using piezoelectric monitoring. Aged mice (15 months) received MW151, a glial cytokine inhibitor (2.5 mg/kg, every other day, 6 weeks).

Results: Only females exhibited midlife reductions in light-phase sleep, increased rhythm fragmentation, and reduced rhythm stability, coinciding with selective reversal learning deficits, effects independent of amyloid or cytokine burden. MW151 increased light-phase sleep and reduced cortical TNF-α without altering amyloid beta (Aβ) accumulation.

Discussion: HAPP^SAA mice recapitulate female-predominant non-cognitive AD features, including sleep fragmentation and circadian instability preceding memory deficits. Sleep improved within weeks of MW151 treatment without Aβ reductions, implicating neuroinflammatory signaling as a rapid, modifiable driver of AD-related sleep disruption.

Document Type

Article

Publication Date

2026

Notes/Citation Information

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2026 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Digital Object Identifier (DOI)

https://doi.org/10.1002/alz.71314

Funding Information

Funding for this study was provided by the National Institutes of Health (R01 AG068215; MPM, MJD, ADB, BFO, SS).

Repository Citation

Macheda, Teresa; Hawkins, Margaret R.; Johnson, Carrie E.; Lapid, Madison G.; Whitlock, Haleigh R.; Shepard, Savannah M.; Cox, MaKayla F.; Roberts, Kelly N.; Bytyqi, Leke; Hash, Heather M.; Abou El-Ezz, Omar A.; Abou El-Ezz, Mohammed; Kohler, Katharina; Sunderam, Sridhar; O'Hara, Bruce F.; Van Eldik, Linda J.; Murphy, Michael Paul; Duncan, Marilyn J.; and Bachstetter, Adam D., "Glial cytokine modulation improves sleep and circadian disruption in female SAA knock-in mice of Alzheimer’s-related pathology" (2026). Neuroscience Faculty Publications. 89.
https://uknowledge.uky.edu/neurobio_facpub/89