Locus coeruleus-norepinephrine system dysfunction: A new concept in cognitive aging and neurodegenerative diseases

The role of the locus coeruleus in aging and neurodegenerative diseases has recently attracted attention. There is growing evidence of changes in the locus coeruleus-norepinephrine system in aging and neurodegenerative diseases, including increased tau accumulation, an inverted U-shaped pattern in the neuromelanin signal, and altered functional connectivity. This review summarizes the research applications and advancements in the study of cognitive aging and dysfunction of the locus coeruleus-norepinephrine system in neurodegenerative diseases. Recent evidence has suggested pathologic protein accumulation, locus coeruleus degeneration, reduced neuromelanin signal, and altered functional connectivity in neurodegenerative diseases in both human and animal models. Notably, the specific regions affected and the severity of these changes can vary subtly among different neurodegenerative disorders. Additionally, recent studies have shown a link between alterations in the locus coeruleus-norepinephrine system and both Alzheimer's and Parkinson's diseases. The possible mechanisms include promoting pathological protein accumulation, pro-inflammatory responses, synaptic plasticity dysfunction, oxidative stress, and blood- brain barrier dysfunction. Advanced experimental technologies have recently been applied to investigate the role of the locus coeruleus-norepinephrine system in aging, Alzheimer's disease, and Parkinson's disease. These advanced technologies, including optogenetic or chemogenetic methods and omics analysis help uncover the effects of specific locus coeruleus activation patterns and the locus coeruleus-related circuit mechanisms underlying its vulnerability during aging and neurodegenerative diseases. Thus, therapies targeting the locus coeruleus-norepinephrine system, including drugs and vagus nerve stimulation, have the potential for clinical application. Many studies have demonstrated the effects of adrenoreceptor-targeted drugs on cognitive function and Parkinson's disease, although some showed no effects. Limited data are available for norepinephrine-targeted drugs, which have demonstrated less-than-ideal results. Recent studies have demonstrated that vagus nerve stimulation can improve cognitive function in Alzheimer's disease and reduce the symptoms of Parkinson's disease, including gait function, suggesting that vagus nerve stimulation could be a new supplementary treatment for neurodegenerative diseases. Overall, the evidence reviewed suggests that the locus coeruleus-norepinephrine system is disrupted during aging and neurodegenerative diseases, and that this disruption can aggravate disease progression. Thus, the locus coeruleus-norepinephrine system is a potential therapeutic target in slowing disease progression. Future studies should focus on the locus coeruleus-norepinephrine system and use advanced experimental and neuroimaging technologies to reveal early pathological alterations and the underlying mechanisms of its vulnerability during aging and neurodegenerative diseases, along with exploring potential therapeutic approaches.