Causes, consequences, and cures for neuroinflammation mediated via the locus coeruleus: noradrenergic signaling system

Abstract

Aside from its roles in as a classical neurotransmitter involved in regulation of behavior, noradrenaline (NA) has other functions in the CNS. This includes restricting the development of neuroinflammatory activation, providing neurotrophic support to neurons, and providing neuroprotection against oxidative stress. In recent years, it has become evident that disruption of physiological NA levels or signaling is a contributing factor to a variety of neurological diseases and conditions including Alzheimer's disease (AD) and Multiple Sclerosis. The basis for dysregulation in these diseases is, in many cases, due to damage occurring to noradrenergic neurons present in the locus coeruleus (LC), the major source of NA in the CNS. LC damage is present in AD, multiple sclerosis, and a large number of other diseases and conditions. Studies using animal models have shown that experimentally induced lesion of LC neurons exacerbates neuropathology while treatments to compensate for NA depletion, or to reduce LC neuronal damage, provide benefit. In this review, we will summarize the anti-inflammatory and neuroprotective actions of NA, summarize examples of how LC damage worsens disease, and discuss several approaches taken to treat or prevent reductions in NA levels and LC neuronal damage. Further understanding of these events will be of value for the development of treatments for AD, multiple sclerosis, and other diseases and conditions having a neuroinflammatory component.

Locus coeruleus cellular and molecular pathology during the progression of Alzheimer’s disease

“…Moreover, NE-dependent modulation of long-term alterations in synaptic strength and gene transcription, particularly within the hippocampus and prefrontal cortex, influences memory formation and experience-dependent alterations in neural function and behavior and plays a critical role in the ability of the LC to optimize performance [105]. Finally, evidence from transgenic mouse models of AD and neuronal cell culture studies show that NE exerts a wide array of neuroprotective effects including anti-inflammatory and pro-neurotrophic mechanisms [32, 43, 44, 58, 64, 72, 74, 117]. Taken together, these data suggest that the central NE projection system is essential for cognitive function and, in turn, that LC neuronal degeneration contributes to cognitive dysfunction.…”

Astrocytic Pathological Calcium Homeostasis and Impaired Vesicle Trafficking in Neurodegeneration

“…A deficit in LC was initially proposed to be associated with the pathogenesis of idiopathic PD; subsequently views on neurodegeneration widened and PD is now viewed as a member of a family of diseases, which are neurological in nature, neurodegenerative in their progressive pathomorphological and functional characteristics and generally associated with ageing [2,4,17]. A sufficient plastic reserve appears to resist the ageing-associated deficits in LC [7].…”

“…This coloration results from the polymerization of noradrenaline (NA) and is analogous to the black dopamine-based neuromelanin. The LC thus is the primary source of NA in the central nervous system (CNS) [2,3,4]. When the LC neurones fire, this results in an activation of astrocytes in the cortex [5,6] and this likely fails to happen when LC is degenerated [2,7].…”

“…The LC thus is the primary source of NA in the central nervous system (CNS) [2,3,4]. When the LC neurones fire, this results in an activation of astrocytes in the cortex [5,6] and this likely fails to happen when LC is degenerated [2,7]. The LC, which contains a relatively small number of neurones (50,000 in adult humans [8]); the axons of these neurones project [3,9,10] to the brain stem, the spinal cord, the cerebellum, the hypothalamus, the hippocampus, the thalamic relay nuclei, the amygdala, the basal telencephalon, and the cortex along distinct bands [10].…”

“…The LC proximal position to the fourth ventricle may further facilitate the exposure of LC neurones to toxins present in the cerebrospinal fluid (CSF) [18]. Therefore, LC nucleus is vulnerable to environmental conditions, which may lead over decades to the development of neurological and neurodegenerative disorders, including Alzheimer’s diseases (AD), Parkinson’s diseases (PD), and other diseases [2,17]. …”