THE LOCUS COERULEUS-NEUROIMMUNE AXIS: A NARRATIVE REVIEW OF MICROGLIAL β₂-AR-P2Y12 CROSSTALK AND SLEEP DISTURBANCES IN ALZHEIMER’S DISEASE

Introduction: Alzheimer’s disease (AD) is characterized by cognitive decline, neuroimmune dysregulation, and sleep disturbances. Locus coeruleus (LC) degeneration in AD leads to sleep-wake disruption and impairs norepinephrine (NE) signaling, which may affect microglial activity through β₂-adrenergic receptors (β₂-ARs). The purinergic receptor P2Y12 also regulates microglial function and sleep homeostasis. However, the relevance of β₂-AR-P2Y12 interactions to AD-related sleep disturbances remains poorly described. Methods: We conducted a narrative review using PubMed/MEDLINE and Google Scholar  to identify English-language studies published between 2021 and 2026 addressing at least two components of the AD-LC-β₂-AR-P2Y12 conceptual axis, complemented by backward citation tracking. Results: Experimental data suggest that β₂-AR agonism leads to anti-inflammatory microglial responses, whereas amyloid β plaques (Aβ) and phosphorylated tau accumulation downregulate this pathway, promoting microglial reactivity. Rodent studies associate P2Y12 signaling with microglial chemotaxis, adenosine production, and reduced availability of extracellular NE, while exposure to Aβ reduces P2Y12 expression. Preliminary evidence supports that P2Y12 may attenuate β₂-AR-mediated microglial responses and sustained β₂-AR activation could suppress P2Y12 signaling through heterologous desensitization and β-arrestin-dependent mechanisms. This bidirectional inhibition potentially contributes to NREM sleep disruption. Conclusion: LC degeneration and β₂-AR-P2Y12 imbalance may collectively contribute to NE dysregulation, microglial dysfunction, sleep disturbances, and proteopathy in AD. However, direct evidence exploring this crosstalk remains limited. Further translational and clinical studies are needed to clarify the mechanisms underlying this interaction and whether it represents a potential therapeutic target for sleep disturbances and neuroimmune dysfunction in AD.