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. Highlights Sleep–wake rhythm disruption is an early hallmark of AD. The LC, one of the earliest AD-vulnerable regions, drives dark phase–specific hyperarousal and impaired brain state transitions in young 5xFAD mice. Soluble Aβ-induced impairment of α2A adrenergic receptor regulation of the Kv4 and Kv7 potassium channels underlies LC hyperexcitability. Pharmacological restoration of α2A–Kv4/7 signaling normalizes LC activity ex vivo and rescues sleep–wake disturbances in vivo. Targeting α2A receptors and Kv7 channels represents a potential strategy for early intervention in AD-related sleep disruption.