Abstract
The locus coeruleus (LC) is a small brainstem nucleus with widely distributed noradrenergic projections to the whole brain, and loss of LC neurons is a prominent feature of age-related neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). This article discusses the hypothesis that in early stages of neurodegenerative diseases, the discharge mode of LC neurons could be changed to a persistent high tonic discharge, which in turn might impair phasic discharge. Since phasic discharge of LC neurons is required for the release of high amounts of norepinephrine (NE) in the brain to promote anti-inflammatory and neuroprotective effects, persistent high tonic discharge of LC neurons could be a key factor in the progression of neurodegenerative diseases. Transcutaneous vagal stimulation (t-VNS), a non-invasive technique that potentially increases phasic discharge of LC neurons, could therefore provide a non-pharmacological treatment approach in specific disease stages. This article focuses on LC vulnerability in neurodegenerative diseases, discusses the hypothesis that a persistent high tonic discharge of LC neurons might affect neurodegenerative processes, and finally reflects on t-VNS as a potentially useful clinical tool in specific stages of AD and PD.
Highlights
The locus coeruleus (LC) is a small nucleus located in the brainstem near the fourth ventricle and is composed of noradrenergic (NAergic) cells
The findings mentioned above suggest that Alzheimer’s disease (AD) and Parkinson’s disease (PD) are both characterized by a significant degeneration of LC neurons, despite having distinct pathologies [22, 106, 121]
Slight differences in LC pathology in AD and PD could be a result of different underlying neuropathological mechanisms that may depend on the internal organization of the LC nucleus, the modulation of neuronal activity and the complexity of axonal projections of LC cells
Summary
The locus coeruleus (LC) is a small nucleus located in the brainstem near the fourth ventricle and is composed of noradrenergic (NAergic) cells. As a protection against these changes, stress-induced increase of NE release triggers auto-inhibitory mechanisms via α2-autoreceptors on LC neurons [78, 95, 96], which induce hyperpolarization and decrease the sensitivity of LC neurons to stimulation. Progressive loss of LC neurons and the concomitant decrease of NE levels in the brain diminish anti-inflammatory and neuroprotective mechanisms and result in an exacerbation of Aβ-induced pro-inflammatory processes and neurotoxicity [31, 109], as well as tau pathology [101, 110]. Decreased NE levels increase αSyn oligomerization, and LC degeneration and αSyn pathology synergistically interact to induce neurodegeneration in PD
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