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

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 hAPPSAA 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: HAPPSAA 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.