Noradrenergic neuromodulation in ageing and disease

Krohn, F.; Lancini, E.; Ludwig, M.; Leiman, M.; Guruprasath, G.; Haag, L.; Panczyszyn, J.; Düzel, E.; Hämmerer, D.; Betts, M.

doi:10.1016/j.neubiorev.2023.105311

Cited by 7 publications

(5 citation statements)

References 325 publications

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“…On the other hand, the substantial reduction of NE-positive neurons within the LC of SMNΔ7 mice is in line with the high vulnerability of this brain nucleus to neuronal degeneration under a neuroinflammatory environment typically occurring in SMA pathology [25][26][27]61 . Accordingly, loss of noradrenergic LC neurons is described in animal models and patients with other neurodegenerative disorders, including multiple sclerosis, Alzheimer's disease, and Parkinson's disease [62][63][64] .…”

Section: Resultsmentioning

confidence: 99%

“…It is well-established that NE is a key regulator of neuroimmune responses, exerting both anti-inflammatory and neuroprotective effects through the activation of noradrenergic receptors located on peripheral immune cells, microglia, and astrocytes 62 . Accordingly, perturbation of NE signaling contributes to the pathophysiology of different inflammatory neurodegenerative disorders [62][63][64] . Based on these findings, we cannot exclude that the anti-inflammatory response elicited by Nusinersen treatment previously reported in the CSF of SMA1 patients 26 could rely on the upregulation of central NE levels identified in this study on the same patients' cohort.…”

Section: Discussionmentioning

confidence: 99%

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SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy

Valsecchi,

Errico,

Bassareo

et al. 2023

Commun Biol

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Beyond motor neuron degeneration, homozygous mutations in the survival motor neuron 1 (SMN1) gene cause multiorgan and metabolic defects in patients with spinal muscular atrophy (SMA). However, the precise biochemical features of these alterations and the age of onset in the brain and peripheral organs remain unclear. Using untargeted NMR-based metabolomics in SMA mice, we identify cerebral and hepatic abnormalities related to energy homeostasis pathways and amino acid metabolism, emerging already at postnatal day 3 (P3) in the liver. Through HPLC, we find that SMN deficiency induces a drop in cerebral norepinephrine levels in overt symptomatic SMA mice at P11, affecting the mRNA and protein expression of key genes regulating monoamine metabolism, including aromatic L-amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DβH) and monoamine oxidase A (MAO-A). In support of the translational value of our preclinical observations, we also discovered that SMN upregulation increases cerebrospinal fluid norepinephrine concentration in Nusinersen-treated SMA1 patients. Our findings highlight a previously unrecognized harmful influence of low SMN levels on the expression of critical enzymes involved in monoamine metabolism, suggesting that SMN-inducing therapies may modulate catecholamine neurotransmission. These results may also be relevant for setting therapeutic approaches to counteract peripheral metabolic defects in SMA.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy

Valsecchi,

Errico,

Bassareo

et al. 2023

Commun Biol

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“…In other species, such as cats, rabbits or dogs, area A5 is less clearly defined [ 15 , 16 ]. In humans, its location is very similar to that of rats, and its alterations seem to be involved in some of the cardiorespiratory manifestations observed in some pathologies, such as Rett syndrome and Ondine disease syndrome, which are currently among the aetiological factors responsible for sudden infant death syndrome [ 17 , 18 , 19 ] or being involved in the neuroinflammation and neuromodulation that mediates various neurodegenerative diseases [ 20 , 21 , 22 , 23 ].…”

Section: Neuroanatomical Overview Of Area A5mentioning

confidence: 99%

Influence of Brainstem’s Area A5 on Sympathetic Outflow and Cardiorespiratory Dynamics

Rocha,

González-García,

Carrillo-Franco

et al. 2024

Biology

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Area A5 is a noradrenergic cell group in the brain stem characterised by its important role in triggering sympathetic activity, exerting a profound influence on the sympathetic outflow, which is instrumental in the modulation of cardiovascular functions, stress responses and various other physiological processes that are crucial for adaptation and survival mechanisms. Understanding the role of area A5, therefore, not only provides insights into the basic functioning of the sympathetic nervous system but also sheds light on the neuronal basis of a number of autonomic responses. In this review, we look deeper into the specifics of area A5, exploring its anatomical connections, its neurochemical properties and the mechanisms by which it influences sympathetic nervous system activity and cardiorespiratory regulation and, thus, contributes to the overall dynamics of the autonomic function in regulating body homeostasis.

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“…with respect to anatomical position and dimensions, LC cell density [8] and to correspond with age-related increases in neuromelanin. [9] Furthermore, associations between LC MRI contrast and AD biomarkers [10] as well as cognitive decline in health and disease have also been observed [5] suggesting neuromelanin-sensitive MRI may be suitable for assessing LC integrity. A reliable extraction of in vivo LC MRI biomarkers requires a robust segmentation approach.…”

Section: Introductionmentioning

confidence: 97%

“…[3] Owing to the early tau aggregation in the LC, assessing the integrity of the LC using structural MRI may be a suitable tool for obtaining pathophysiological insights in vivo. [4,5] It presents an opportunity to gain insights into cognitive and behavioral symptoms instrumental for developing effective treatments [1], improve our understanding of AD pathogenesis and facilitate the development of diseasemodifying noradrenergic drugs. [6] So-called neuromelanin-sensitve Magnetic Resonance Imaging (MRI) techniques permit the in vivo visualization of the LC by exploiting the magnetic properties of its neuromelanin pigmented neurons although the exact mechanisms remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Fully Automated MRI-based Analysis of the Locus Coeruleus in Aging and Alzheimer’s Disease Dementia using ELSI-Net

Dünnwald,

Krohn,

Sciarra

et al. 2024

Preprint

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INTRODUCTION: The Locus Coeruleus (LC) is linked to the development and pathophysiology of neurodegenerative diseases such as Alzheimer's Disease (AD). Magnetic Resonance Imaging based LC features have shown potential to assess LC integrity in vivo. METHODS: We present a Deep Learning based LC segmentation and feature extraction method: ELSI-Net and apply it to healthy aging and AD dementia datasets. Agreement to expert raters and previously published LC atlases were assessed. We aimed to reproduce previously reported differences in LC integrity in aging and AD dementia and correlate extracted features to cerebrospinal fluid (CSF) biomarkers of AD pathology. RESULTS: ELSI-Net demonstrated high agreement to expert raters and published atlases. Previously reported group differences in LC integrity were detected and correlations to CSF biomarkers were found. DISCUSSION: Although we found excellent performance, further evaluations on more diverse datasets from clinical cohorts are required for a conclusive assessment of ELSI-Nets general applicability.

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Noradrenergic neuromodulation in ageing and disease

Cited by 7 publications

References 325 publications

SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy

SMN deficiency perturbs monoamine neurotransmitter metabolism in spinal muscular atrophy

Influence of Brainstem’s Area A5 on Sympathetic Outflow and Cardiorespiratory Dynamics

Fully Automated MRI-based Analysis of the Locus Coeruleus in Aging and Alzheimer’s Disease Dementia using ELSI-Net

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