Noradrenaline in Alzheimer's Disease: A New Potential Therapeutic Target.

A growing body of evidence demonstrates the important role of the noradrenergic system in the pathogenesis of many neurodegenerative processes, especially Alzheimer's disease, due to its ability to control glial activation and chemokine production resulting in anti-inflammatory and neuroprotective effects. Noradrenaline involvement in this disease was first proposed after finding deficits of noradrenergic neurons in the locus coeruleus from Alzheimer's disease patients. Based on this, it has been hypothesized that the early loss of noradrenergic projections and the subsequent reduction of noradrenaline brain levels contribute to cognitive dysfunctions and the progression of neurodegeneration. Several studies have focused on analyzing the role of noradrenaline in the development and progression of Alzheimer's disease. In this review we summarize some of the most relevant data describing the alterations of the noradrenergic system normally occurring in Alzheimer's disease as well as experimental studies in which noradrenaline concentration was modified in order to further analyze how these alterations affect the behavior and viability of different nervous cells. The combination of the different studies here presented suggests that the maintenance of adequate noradrenaline levels in the central nervous system constitutes a key factor of the endogenous defense systems that help prevent or delay the development of Alzheimer's disease. For this reason, the use of noradrenaline modulating drugs is proposed as an interesting alternative therapeutic option for Alzheimer's disease.

Locus Coeruleus Shows a Spatial Pattern of Structural Disintegration in Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) causes a loss of neuromelanin-positive, noradrenergic neurons in the locus coeruleus (LC), which has been implicated in nonmotor dysfunction. OBJECTIVES: We used "neuromelanin sensitive" magnetic resonance imaging (MRI) to localize structural disintegration in the LC and its association with nonmotor dysfunction in PD. METHODS: A total of 42 patients with PD and 24 age-matched healthy volunteers underwent magnetization transfer weighted (MTw) MRI of the LC. The contrast-to-noise ratio of the MTw signal (CNRMTw ) was used as an index of structural LC integrity. We performed slicewise and voxelwise analyses to map spatial patterns of structural disintegration, complemented by principal component analysis (PCA). We also tested for correlations between regional CNRMTw and severity of nonmotor symptoms. RESULTS: Mean CNRMTw of the right LC was reduced in patients relative to controls. Voxelwise and slicewise analyses showed that the attenuation of CNRMTw was confined to the right mid-caudal LC and linked regional CNRMTw to nonmotor symptoms. CNRMTw attenuation in the left mid-caudal LC was associated with the orthostatic drop in systolic blood pressure, whereas CNRMTw attenuation in the caudal most portion of right LC correlated with apathy ratings. PCA identified a bilateral component that was more weakly expressed in patients. This component was characterized by a gradient in CNRMTw along the rostro-caudal and dorso-ventral axes of the nucleus. The individual expression score of this component reflected the overall severity of nonmotor symptoms. CONCLUSION: A spatially heterogeneous disintegration of LC in PD may determine the individual expression of specific nonmotor symptoms such as orthostatic dysregulation or apathy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Examining the Role of the Noradrenergic Locus Coeruleus for Predicting Attention and Brain Maintenance in Healthy Old Age and Disease: An MRI Structural Study for the Alzheimer's Disease Neuroimaging Initiative.

The noradrenergic theory of Cognitive Reserve (Robertson, 2013-2014) postulates that the upregulation of the locus coeruleus-noradrenergic system (LC-NA) originating in the brainstem might facilitate cortical networks involved in attention, and protracted activation of this system throughout the lifespan may enhance cognitive stimulation contributing to reserve. To test the above-mentioned theory, a study was conducted on a sample of 686 participants (395 controls, 156 mild cognitive impairment, 135 Alzheimer's disease) investigating the relationship between LC volume, attentional performance and a biological index of brain maintenance (BrainPAD-an objective measure, which compares an individual's structural brain health, reflected by their voxel-wise grey matter density, to the state typically expected at that individual's age). Further analyses were carried out on reserve indices including education and occupational attainment. Volumetric variation across groups was also explored along with gender differences. Control analyses on the serotoninergic (5-HT), dopaminergic (DA) and cholinergic (Ach) systems were contrasted with the noradrenergic (NA) hypothesis. The antithetic relationships were also tested across the neuromodulatory subcortical systems. Results supported by Bayesian modelling showed that LC volume disproportionately predicted higher attentional performance as well as biological brain maintenance across the three groups. These findings lend support to the role of the noradrenergic system as a key mediator underpinning the neuropsychology of reserve, and they suggest that early prevention strategies focused on the noradrenergic system (e.g., cognitive-attentive training, physical exercise, pharmacological and dietary interventions) may yield important clinical benefits to mitigate cognitive impairment with age and disease.

Alzheimer's disease: An evolving understanding of noradrenergic involvement and the promising future of electroceutical therapies.

Alzheimer's disease (AD) poses a significant global health concern over the next several decades. Multiple hypotheses have been put forth that attempt to explain the underlying pathophysiology of AD. Many of these are briefly reviewed here, but to-date no disease-altering therapy has been achieved. Despite this, recent work expanding on the role of noradrenergic system dysfunction in both the pathogenesis and symptomatic exacerbation of AD has shown promise. The role norepinephrine (NE) plays in AD remains complicated but pre-tangle tau has consistently been shown to arise in the locus coeruleus (LC) of patients with AD decades before symptom onset. The current research reviewed here indicates NE can facilitate neuroprotective and memory-enhancing effects through ß adrenergic receptors, while α2A adrenergic receptors may exacerbate amyloid toxicity through a contribution to tau hyperphosphorylation. AD appears to involve a disruption in the balance between these two receptors and their various subtypes. There is also a poorly characterized interplay between the noradrenergic and cholinergic systems. LC deterioration leads to maladaptation in the remaining LC-NE system and subsequently inhibits cholinergic neuron function, eventually leading to the classic cholinergic disruption seen in AD. Understanding AD as a dysfunctional noradrenergic system, provides new avenues for the use of advanced neural stimulation techniques to both study and therapeutically target the earliest stages of neuropathology. Direct LC stimulation and non-invasive vagus nerve stimulation (VNS) have both demonstrated potential use as AD therapeutics. Significant work remains, though, to better understand the role of the noradrenergic system in AD and how electroceuticals can provide disease-altering treatments.

The Cholinergic System, the Adrenergic System and the Neuropathology of Alzheimer's Disease.

Neurodegenerative diseases are a major public health problem worldwide with a wide spectrum of symptoms and physiological effects. It has been long reported that the dysregulation of the cholinergic system and the adrenergic system are linked to the etiology of Alzheimer's disease. Cholinergic neurons are widely distributed in brain regions that play a role in cognitive functions and normal cholinergic signaling related to learning and memory is dependent on acetylcholine. The Locus Coeruleus norepinephrine (LC-NE) is the main noradrenergic nucleus that projects and supplies norepinephrine to different brain regions. Norepinephrine has been shown to be neuroprotective against neurodegeneration and plays a role in behavior and cognition. Cholinergic and adrenergic signaling are dysregulated in Alzheimer's disease. The degeneration of cholinergic neurons in nucleus basalis of Meynert in the basal forebrain and the degeneration of LC-NE neurons were reported in Alzheimer's disease. The aim of this review is to describe current literature on the role of the cholinergic system and the adrenergic system (LC-NE) in the pathology of Alzheimer's disease and potential therapeutic implications.

Preserved noradrenergic function in Parkinson's disease patients with rest tremor.

Noradrenergic neurotransmission may play an important role in tremor modulation through its innervation of key structures of the central tremor circuits. Here, Parkinson's disease (PD) patients with (PDT+) or without (PDT-) rest tremor had 11C-methylreboxetine(11C-MeNER) positron emission tomography (PET) to test the hypothesis that noradrenaline terminal function was relatively preserved in PDT+ compared to PDT-. METHODS: Sixty-five PD patients and 28 healthy controls (HC) were scanned with 11C-MeNER PET. Patients were categorized as PDT+ if subscores in UPDRS-III item 3 or MDS-UPDRS-III item 17 was ≥2; remaining were categorized as PDT-. Simplified reference tissue model 2 distribution volume ratios (DVR) for 11C-MeNER were calculated for thalamus, dorsal and median raphe, locus coeruleus (LC) and red nucleus using time activity curves (TACs) obtained from volumes of interest (VOI). Data were statistically interrogated with a general linear mixed model using 'region', and 'group' as factors and the interaction of 'region x group' was examined. RESULTS: Tremor positive PD patients had a significantly higher mean 11C-MeNER DVR compared to PDT- in LC and thalamus. The PDT+ mean LC DVR was similar to that of HC. PDT+ mean 11C-MeNER DVRs were significantly lower than HC in the dorsal raphe while the PDT- group showed significantly lower mean 11C-MeNER DVR across all regions compared to HC. CONCLUSION: While both PD T+ and PD T- groups showed a significant loss of noradrenaline terminal function compared to controls, noradrenergic neurons were relatively preserved in PDT+ in LC and thalamus. The greater loss of noradrenergic transporters in PDT- in LC and thalamus compared with PDT+ is in line with earlier in-vitro studies and could potentially contribute to their tremor negative phenotype.

Combination of tumor necrosis factor-α and epidermal growth factor induces the adrenergic-to-mesenchymal transdifferentiation in SH-SY5Y neuroblastoma cells.

Neuroblastoma, a type of cancer that is common in children, is composed of two genetically clonal but epigenetically distinct cell types: mesenchymal (MES) and adrenergic (ADRN) types, controlled by super-enhancer-associated lineage-specific transcription factor networks. Mesenchymal-type cells are more migratory, resistant to chemotherapy, and prevalent in relapse tumors. Importantly, both cell types spontaneously transdifferentiate into one another, and this interconversion can be induced by genetic manipulations. However, the mechanisms of their spontaneous transdifferentiation and extracellular factors inducing this phenomenon have not yet been elucidated. Using a unique approach involving gene set enrichment analysis, we selected six ADRN and 10 MES candidate factors, possibly inducing ADRN and MES phenotypes, respectively. Treatment with a combination of 10 MES factors clearly induced the MES gene expression profile in ADRN-type SH-SY5Y neuroblastoma cells. Considering the effects on gene expression profile, migration ability, and chemoresistance, a combination of tumor necrosis factor alpha (TNF-α) and epidermal growth factor (EGF) was sufficient to synergistically induce the ADRN-to-MES transdifferentiation in SH-SY5Y cells. In addition, human neuroblastoma cohort analysis revealed that the expression of TNF and EGF receptors was strongly associated with MES gene expression signatures, supporting their important roles in transdifferentiation in vivo. Collectively, we propose a mechanism of neuroblastoma transdifferentiation induced by extracellular growth factors, which can be controlled in clinical situations, providing a new therapeutic possibility.

Intrinsic braking role of descending locus coeruleus noradrenergic neurons in acute and chronic itch in mice.

Itch is defined as an unpleasant sensation that provokes a desire to scratch. Our understanding of neuronal circuits for itch information transmission and processing in the spinal dorsal horn (SDH) has progressively advanced following the identification of SDH neuron subsets that are crucial for scratching behavior in models of itch. However, little is known about the control of acute and chronic itch by descending signals from the brain to the SDH. In this study, using genetic approaches that enable cell-type and circuit-specific functional manipulation, we reveal an intrinsic potential of locus coeruleus (LC)-noradrenergic (NAergic) neurons that project to the SDH to control acute and chronic itch. Activation and silencing of SDH-projecting LC-NAergic neurons reduced and enhanced scratching behavior, respectively, in models of histamine-dependent and -independent acute itch. Furthermore, in a model of chronic itch associated with contact dermatitis, repetitive scratching behavior was suppressed by the activation of the descending LC-NAergic pathway and by knocking out NA transporters specific to descending LC-NAergic neurons using a CRISPR-Cas9 system. Moreover, patch-clamp recording using spinal slices showed that noradrenaline facilitated inhibitory synaptic inputs onto gastrin-releasing peptide receptor-expressing SDH neurons, a neuronal subset known to be essential for itch transmission. Our findings suggest that descending LC-NAergic signaling intrinsically controls acute and chronic itch and provide potential therapeutic strategies for the treatment of acute and chronic itch.

Transgenic Mice Expressing Human α-Synuclein in Noradrenergic Neurons Develop Locus Ceruleus Pathology and Nonmotor Features of Parkinson's Disease.

Degeneration of locus ceruleus (LC) neurons and dysregulation of noradrenergic signaling are ubiquitous features of Parkinson's disease (PD). The LC is among the first brain regions affected by α-synuclein (asyn) pathology, yet how asyn affects these neurons remains unclear. LC-derived norepinephrine (NE) can stimulate neuroprotective mechanisms and modulate immune cells, while dysregulation of NE neurotransmission may exacerbate disease progression, particularly nonmotor symptoms, and contribute to the chronic neuroinflammation associated with PD pathology. Although transgenic mice overexpressing asyn have previously been developed, transgene expression is usually driven by pan-neuronal promoters and thus has not been selectively targeted to LC neurons. Here we report a novel transgenic mouse expressing human wild-type asyn under control of the noradrenergic-specific dopamine ß-hydroxylase promoter (DBH-hSNCA). These mice developed oligomeric and conformation-specific asyn in LC neurons, alterations in hippocampal and LC microglial abundance, upregulated GFAP expression, degeneration of LC fibers, decreased striatal DA metabolism, and age-dependent behaviors reminiscent of nonmotor symptoms of PD that were rescued by adrenergic receptor antagonists. These mice provide novel insights into how asyn pathology affects LC neurons and how central noradrenergic dysfunction may contribute to early PD pathophysiology.SIGNIFICANCE STATEMENT ɑ-Synuclein (asyn) pathology and loss of neurons in the locus ceruleus (LC) are two of the most ubiquitous neuropathologic features of Parkinson's disease (PD). Dysregulated norepinephrine (NE) neurotransmission is associated with the nonmotor symptoms of PD, including sleep disturbances, emotional changes such as anxiety and depression, and cognitive decline. Importantly, the loss of central NE may contribute to the chronic inflammation in, and progression of, PD. We have generated a novel transgenic mouse expressing human asyn in LC neurons to investigate how increased asyn expression affects the function of the central noradrenergic transmission and associated behaviors. We report cytotoxic effects of oligomeric and conformation-specific asyn, astrogliosis, LC fiber degeneration, disruptions in striatal dopamine metabolism, and age-dependent alterations in nonmotor behaviors without inclusions.

Calbindin-D28K, parvalbumin, and calretinin in young and aged human locus coeruleus.

Certain neuronal populations, including basal forebrain cholinergic neurons (BFCN) and noradrenergic neurons of the locus coeruleus (LC), are selectively vulnerable to pathology and loss early in the course of aging and Alzheimer's disease (AD). Human BFCN show substantial loss of the calcium-binding protein (CBP), calbindin-D28K (CB), during normal aging, which is associated with formation of neurofibrillary tangles and BFCN loss in AD. Here we determined if, similar to the BFCN, LC neurons contain CB or the other 2 ubiquitous CBPs parvalbumin and calretinin, and whether these proteins display an age-related loss from LC neurons. Immunostaining for CBP and tyrosine hydroxylase, a marker of catecholaminergic neurons, was used in sections from the LC of young and aged human brains. Parvalbumin and calretinin immunoreactivities were completely absent from human LC neurons. A subpopulation of LC neurons (~10%) contained CB immunoreactivity. Quantitative analysis revealed no age-related loss of CB from LC neurons. Thus, unlike the BFCN, age-related loss of CB does not figure prominently in the selective vulnerability of LC neurons to degeneration in AD.

Integrin CD11b mediates locus coeruleus noradrenergic neurodegeneration in a mouse Parkinson's disease model.

BACKGROUND: The loss of locus coeruleus noradrenergic (LC/NE) neurons in the brainstem is reported in multiple neurodegenerative disorders, including Parkinson's disease (PD). However, the mechanisms remain unclear. Strong evidence suggested that microglia-mediated neuroinflammation contributes to neurodegeneration in PD. We recently recognized integrin CD11b, the α-chain of macrophage antigen complex-1 (Mac-1, also called CR3), as a key regulator for microglial activation. However, whether CD11b is involved in LC/NE neurodegeneration in PD remains to be investigated. METHODS: LC/NE neurodegeneration and microglial activation were compared between wild type (WT) and CD11b KO mice after treated with paraquat and maneb, two pesticides that widely used to create PD model. The role of NLRP3 inflammasome in CD11b-mediated microglial dysfunction and LC/NE neurodegeneration was further explored. LC/NE neurodegeneration, microglial phenotype, and NLRP3 inflammasome activation were determined by using Western blot, immunohistochemistry, and RT-PCR technologies. RESULTS: Paraquat and maneb co-exposure elevated the expressions of CD11b in the brainstem of mice, and CD11b knockout significantly reduced LC/NE neurodegeneration induced by paraquat and maneb. Mitigated microglial activation and gene expressions of proinflammatory cytokines were also observed in paraquat and maneb-treated CD11b-/- mice. Mechanistically, CD11b-mediated NLRP3 inflammasome activation contributes to paraquat and maneb-induced LC/NE neurodegeneration. Compared with WT controls, CD11b deficiency reduced paraquat and maneb-induced NLRP3 expression, caspase-1 activation, and interleukin-1ß production in mice. Furthermore, inhibition of NLRP3 inflammasome by glybenclamide, a sulfonylurea inhibitor of NLRP3 inflammasome, was found to be able to suppress microglial proinflammatory activation and nuclear factor-κB activation induced by paraquat and maneb. Moreover, reduced reactive oxygen species production, NADPH oxidase, and inducible nitric oxide synthase expressions as well as 4-hydroxynonenal and malondialdehyde levels were detected in combined glybenclamide and paraquat and maneb-treated mice compared with paraquat and maneb alone group. Finally, we found that glybenclamide treatment ameliorated LC/NE neurodegeneration and α-synuclein aggregation in paraquat and maneb-treated mice. CONCLUSION: Our findings suggested that CD11b mediates LC/NE neurodegeneration through NLRP3 inflammation-dependent microglial proinflammatory activation in a two pesticide-induced mouse PD model, providing a novel insight into the immune pathogenesis of LC/NE neuronal damage in related disorders.

MPTP-Induced Impairment of Cardiovascular Function.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of Lewy bodies and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpC). MPTP is widely used to generate murine PD model. In addition to classical motor disorders, PD patients usually have non-motor symptoms related to autonomic impairment, which precedes decades before the motor dysfunction. This study's objective is to examine the effects of MPTP on noradrenergic neurons in the hindbrain, thereby on the cardiovascular function in mice. Adult mice received 10 mg/kg/day of MPTP (4 consecutive days) to generate PD model. Systolic blood pressure was measured by tail cuff system in conscious mice, and baroreflex sensitivity was evaluated by heart rate alteration in response to a transient increase or decrease in blood pressure induced by intravenous infusion of phenylalanine (PE) or sodium nitroprusside (SNP) in anesthetized condition, respectively. Baseline heart rate and heart rate variability were analyzed in both sham and MPTP-treated mice. Dopamine, norepinephrine, and related metabolites in the plasma and brain tissues including SNpC, locus coeruleus (LC), rostroventrolateral medulla (RVLM), and nucleus tractus solitarii (NTS) were measured by liquid chromatography-mass spectrometry (LC-MS). Tyrosine hydroxylase-positive (TH+) neurons in above nuclei were quantified by immunoreactivities. We found that in addition to the loss of TH+ neurons in SNpC, MPTP treatment induced a dramatic reduction of TH+ cell counts in the LC, RVLM, and NTS. These are associated with significant decreases of dopamine, norepinephrine, and epinephrine in above nuclei. Meanwhile, MPTP induced a lasting effect of baroreflex desensitization, tachycardia, and decreased heart rate variability compared to the sham mice. Notably, MPTP treatment elevated sympathetic outflow and suppressed parasympathetic tonicity according to the heart rate power spectrum analysis. Our results indicate that the loss of TH+ neurons in the brainstem by MPTP treatment led to impaired autonomic cardiovascular function. These results suggest that MPTP treatment can be used to study the autonomic dysfunction in murine model.

Exposure to acrylamide decreases noradrenergic axons in rat brain.

PURPOSE: Acrylamide is known to induce disorders in the central nervous system in humans and experimental animals. The present study investigated effects of exposure to acrylamide on adult neurogenesis, noradrenergic axons and the level of norepinephrine in the brain of male rats. METHOD: Four groups of 12 male Wistar rats each were exposed to acrylamide at 0, 0.2, 2 and 20 mg/kg body weight by gavage for 5 weeks. Six rats of each groups were injected with 5-bromo-2'-deoxy-uridine (BrdU) after five-week exposure to acrylamide to examine proliferative cells in the dentate gyrus using immunostaining. Density of noradrenergic and serotonergic axons in the prefrontal cortex, hippocampus and cortex behind the bregma was quantified. Remaining 6 rats were decapitated after the last exposure and brains were dissected out to measure monoamine level in the hippocampus and prefrontal cortex using high performance liquid chromatography. RESULT: Exposure to acrylamide dose-dependently decreased the density of noradrenergic axons in the prefrontal cortex with a significant change at 20 mg/kg. Norepinephrine level decreased in the hippocampus at 20 mg/kg. Exposure to acrylamide at 20 mg/kg or less did not change the number of BrdU positive cells, but the result should be considered preliminary. CONCLUSION: The results show that oral exposure to acrylamide induces decrease in noradrenergic axons and norepinephrine level in the brain of rats. Given the similar effects are observed in 1-bromopropane-exposed rats, there may be the common mechanism in the toxicity of soft electrophiles to the central nervous system.

Locus coeruleus pathology in progressive supranuclear palsy, and its relation to disease severity.

The locus coeruleus is the major source of noradrenaline to the brain and contributes to a wide range of physiological and cognitive functions including arousal, attention, autonomic control, and adaptive behaviour. Neurodegeneration and pathological aggregation of tau protein in the locus coeruleus are early features of progressive supranuclear palsy (PSP). This pathology is proposed to contribute to the clinical expression of disease, including the PSP Richardson's syndrome. We test the hypothesis that tau pathology and neuronal loss are associated with clinical heterogeneity and severity in PSP.We used immunohistochemistry in post mortem tissues from 31 patients with a clinical diagnosis of PSP (22 with Richardson's syndrome) and 6 control cases. We quantified the presence of hyperphosphorylated tau, the number of pigmented cells indicative of noradrenergic neurons, and the percentage of pigmented neurons with tau-positive inclusions. Ante mortem assessment of clinical severity using the PSP rating scale was available within 1.8 (±0.9) years for 23 patients.We found an average 49% reduction of pigmented neurons in PSP patients relative to controls. The loss of pigmented neurons correlated with disease severity, even after adjusting for disease duration and the interval between clinical assessment and death. The degree of neuronal loss was negatively associated with tau-positive inclusions, with an average of 44% of pigmented neurons displaying tau-inclusions.Degeneration and tau pathology in the locus coeruleus are related to clinical heterogeneity of PSP. The noradrenergic deficit in the locus coeruleus is a candidate target for pharmacological treatment. Recent developments in ultra-high field magnetic resonance imaging to quantify in vivo structural integrity of the locus coeruleus may provide biomarkers for noradrenergic experimental medicines studies in PSP.

Loss of p53 drives neuron reprogramming in head and neck cancer.

The solid tumour microenvironment includes nerve fibres that arise from the peripheral nervous system1,2. Recent work indicates that newly formed adrenergic nerve fibres promote tumour growth, but the origin of these nerves and the mechanism of their inception are unknown1,3. Here, by comparing the transcriptomes of cancer-associated trigeminal sensory neurons with those of endogenous neurons in mouse models of oral cancer, we identified an adrenergic differentiation signature. We show that loss of TP53 leads to adrenergic transdifferentiation of tumour-associated sensory nerves through loss of the microRNA miR-34a. Tumour growth was inhibited by sensory denervation or pharmacological blockade of adrenergic receptors, but not by chemical sympathectomy of pre-existing adrenergic nerves. A retrospective analysis of samples from oral cancer revealed that p53 status was associated with nerve density, which was in turn associated with poor clinical outcomes. This crosstalk between cancer cells and neurons represents mechanism by which tumour-associated neurons are reprogrammed towards an adrenergic phenotype that can stimulate tumour progression, and is a potential target for anticancer therapy.

Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus.

Aberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer's disease-like (AD-like) neuropathology in the human brain. However, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear. Here, we show that 3,4-dihydroxyphenylglycolaldehyde, which is produced exclusively in noradrenergic neurons by monoamine oxidase A metabolism of norepinephrine, activated asparagine endopeptidase that cleaved Tau at residue N368 into aggregation- and propagation-prone forms, thus leading to LC degeneration and the spread of Tau pathology. Activation of asparagine endopeptidase-cleaved Tau aggregation in vitro and in intact cells was triggered by 3,4-dihydroxyphenylglycolaldehyde, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal that norepinephrine metabolism and Tau cleavage represent the specific molecular mechanism underlying the selective vulnerability of LC neurons in AD.

Noradrenergic Regulation of Hippocampus-Dependent Memory.

Neuromodulation regulates critical functions of CNS synapses, ranging from neural circuit development to high-order cognitive processes, including learning and memory. This broad scope of action is generally mediated through alterations of the strength of synaptic transmission (i.e. synaptic plasticity). Changes in synaptic strength are widely considered to be a cellular representation of learned information. Noradrenaline is a neuromodulator that is secreted throughout the brain in response to novelty or increased arousal. Once released, noradrenaline activates metabotropic receptors, initiating intracellular signaling cascades that promote enduring changes in synaptic strength and facilitate memory storage. Here, we provide an overview of noradrenergic modulation of synaptic plasticity and memory formation within mammalian neural circuits, which has broad applicability within the neurotherapeutics community. Advances in our understanding of noradrenaline in the context of these processes may provide a foundation for refining treatment strategies for multiple brain diseases, ranging from post-traumatic stress disorder to Alzheimer's Disease.

Noradrenergic dysfunction accelerates LPS-elicited inflammation-related ascending sequential neurodegeneration and deficits in non-motor/motor functions.

The loss of central norepinephrine (NE) released by neurons of the locus coeruleus (LC) occurs with aging, and is thought to be an important factor in producing the many of the nonmotor symptoms and exacerbating the degenerative process in animal models of Parkinson's disease (PD). We hypothesize that selectively depleting noradrenergic LC neurons prior to the induction of chronic neuroinflammation may not only accelerate the rate of progressive neurodegeneration throughout the brain, but may exacerbate nonmotor and motor behavioral phenotypes that recapitulate symptoms of PD. For this reason, we used a "two-hit" mouse model whereby brain NE were initially depleted by DSP-4 one week prior to exposing mice to LPS. We found that pretreatment with DSP-4 potentiated LPS-induced sequential neurodegeneration in SNpc, hippocampus, and motor cortex, but not in VTA and caudate/putamen. Mechanistic study revealed that DSP-4 enhanced LPS-induced microglial activation and subsequently elevated neuronal oxidative stress in affected brain regions in a time-dependent pattern. To further characterize the effects of DSP-4 on non-motor and motor symptoms in the LPS model, physiological and behavioral tests were performed at different time points following injection. Consistent with the enhanced neurodegeneration, DSP-4 accelerated the progressive deficits of non-motor symptoms including hyposmia, constipation, anxiety, sociability, exaggerated startle response and impaired learning. Furthermore, notable decreases of motor functions, including decreased rotarod activity, grip strength, and gait disturbance, were observed in treated mice. In summary, our studies provided not only an accelerated "two-hit" PD model that recapitulates the features of sequential neuron loss and the progression of motor/non-motor symptoms of PD, but also revealed the critical role of early LC noradrenergic neuron damage in the pathogenesis of PD-like symptoms.