α2A-AR-Kv dysfunction drives LC hyperactivity and early sleep disturbance in amyloidogenic mice
Disrupted sleep-wake patterns are common in neurodegenerative disorders such as Alzheimer's disease (AD), can emerge early, and are proposed as potent risk factors for disease onset and progression. However, the underlying mechanisms remain poorly understood. Here, we report that 5xFAD transgenic mice exhibit hyperarousal and reduced brain-state transitions, particularly during the dark phase, as early as two months of age. The Locus Coeruleus (LC), a key regulator of arousal and brain-state transitions and a region highly vulnerable in AD, shows time-specific hyperactivity during this phase. This increased tonic LC activity is mediated by heightened neuronal excitability due to impaired Kv4 and Kv7 potassium channel conductance. Pharmacological activation of 2A adrenergic receptors restored Kv4 and Kv7 function and normalized LC activity. Furthermore, local administration of the 2A agonist guanfacine or the Kv7 positive allosteric modulator retigabine substantially rescued the sleep-wake disturbances in young 5xFAD mice. These findings identify dark-phase-selective LC hyperexcitability as a key driver of early-onset sleep disruption in AD mice and implicate 2A adrenergic receptors and Kv7 channels as promising targets for early intervention.