Impaired adrenergic regulation of Kv channels underlies LC hyperactivity and early-onset sleep disruption in AD-like amyloidogenic mice.

Abstract

INTRODUCTION: Sleep-wake disturbances frequently occur at early stages of Alzheimer's disease (AD) and accelerate disease progression, but the underlying neural mechanisms are not fully understood. METHODS: We examined sleep-wake behavior and locus coeruleus (LC) activity in young 5xFAD mice using electrophysiology and pharmacological approaches targeting adrenergic signaling and potassium channels. RESULTS: 5xFAD mice displayed dark phase-specific hyperarousal and impaired brain state transitions by 2 months of age. LC neurons exhibited increased tonic firing due to impaired Kv4 and Kv7 potassium channel conductance, resulting from soluble amyloid beta (Aβ)-induced disruption of α2A adrenergic receptor regulation. Pharmacological activation of α2A adrenergic receptors restored Kv4/7 function and normalized LC excitability. Local administration of guanfacine (α2A agonist) or retigabine (Kv7 modulator) significantly rescued sleep-wake disturbances. DISCUSSION: These findings identify LC hyperexcitability as a mechanistic driver of early sleep disruption in AD and implicate α2A receptors and Kv7 channels as promising therapeutic targets for early intervention.