Preventing neurodegeneration by adrenergic astroglial excitation

Zorec, Robert; Parpura, Vladimir; Verkhratsky, Alexei

doi:10.1111/febs.14456

Cited by 30 publications

(27 citation statements)

References 132 publications

(213 reference statements)

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“…Astrocytes appear to be the primary target of NA, an important neuromodulator in the CNS [28][29][30]40 . Through binding to ARs on the surface of astrocytes, NA activates cAMP and Ca 2+ signaling 37,39,56 , which may be dysregulated in various neurologic disorders 32,[57][58][59][60] . To study whether ALS-and FTD-U-linked TDP-43 inclusions affect cAMP and Ca 2+ signaling, we monitored NA-induced changes in [cAMP] i and [Ca 2+ ] i using real-time confocal microscopy and genetically encoded FRET-based cAMP nanosensor Epac1-camps 53 or Fluo-4 AM dye, respectively, in astrocytes expressing WT (RFP-TDP-43 wt ) or mutant TDP-43 pDNA construct (RFP-TDP-43 ; Figs.…”

Section: Noradrenaline-mediated Increases In [Camp] I and [Ca 2+mentioning

confidence: 99%

Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism

Velebit

Horvat

Smolič

et al. 2020

Sci Rep

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Most cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) in neurons and non-neuronal cells, including astrocytes, which metabolically support neurons with nutrients. Neuronal metabolism largely depends on the activation of the noradrenergic system releasing noradrenaline. Activation of astroglial adrenergic receptors with noradrenaline triggers cAMP and Ca 2+ signaling and augments aerobic glycolysis with production of lactate, an important neuronal energy fuel. Astrocytes with cytoplasmic TDP-43 inclusions can cause motor neuron death, however, whether astroglial metabolism and metabolic support of neurons is altered in astrocytes with TDP-43 inclusions, is unclear. We measured lipid droplet and glucose metabolisms in astrocytes expressing the inclusion-forming C-terminal fragment of TDP-43 or the wild-type TDP-43 using fluorescent dyes or genetically encoded nanosensors. Astrocytes with TDP-43 inclusions exhibited a 3-fold increase in the accumulation of lipid droplets versus astrocytes expressing wild-type TDP-43, indicating altered lipid droplet metabolism. In these cells the noradrenaline-triggered increases in intracellular cAMP and Ca 2+ levels were reduced by 35% and 31%, respectively, likely due to the downregulation of β 2-adrenergic receptors. Although noradrenaline triggered a similar increase in intracellular lactate levels in astrocytes with and without TDP-43 inclusions, the probability of activating aerobic glycolysis was facilitated by 1.6-fold in astrocytes with TDP-43 inclusions and lactate MCT1 transporters were downregulated. Thus, while in astrocytes with TDP-43 inclusions noradrenergic signaling is reduced, aerobic glycolysis and lipid droplet accumulation are facilitated, suggesting dysregulated astroglial metabolism and metabolic support of neurons in TDP-43-associated ALS and FTD. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of both upper and lower motor neurons in the brain and spinal cord, and by the progressive paralysis of voluntary muscles and death 1,2. The pathologic hallmark of ALS are cytoplasmic inclusions in motor neurons. In most cases (~95%) of sporadic and familial ALS, TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the key component of these inclusions 1-9. Moreover, TDP-43 has also been identified as the major protein in inclusions in frontotemporal dementia with ubiquitin-positive inclusions (FTD-U) 2,6. TDP-43 is a highly conserved protein (414 amino acids), ubiquitously expressed in all tissues and under physiological conditions, primarily localized to the nucleus; however, low levels are also present in the cytoplasm 2,3,8,10-13. TDP-43, an RNA-binding protein, is implicated in multiple aspects of RNA processing, including regulation of transcription, splicing, transport, and stabilization of mRNAs. It also regulates microRNA biogenesis and interacts with DNA. Therefore, its perturbance ...

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Section: Noradrenaline-mediated Increases In [Camp] I and [Ca 2+mentioning

confidence: 99%

Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism

Velebit

Horvat

Smolič

et al. 2020

Sci Rep

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“…In addition, this process suppresses neurogenesis, which further impairs neuronal plasticity [231,237]. Apart from the cholinergic system, AD pathology impairs other major neurotransmitter systems including noradrenergic, serotonergic and dopaminergic [153,234,348].…”

Section: Senile Dementia-the Outcome Of Pathological Ageingmentioning

confidence: 99%

Astroglia in Alzheimer’s Disease

Verkhratsky

Parpura

Rodriguez-Arellano

et al. 2019

Advances in Experimental Medicine and Biology

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Alzheimer's disease is the most common cause of dementia. Cellular changes in the brains of the patients suffering from Alzheimer's disease occur well in advance of the clinical symptoms. At the cellular level, the most dramatic is a demise of neurones. As astroglial cells carry out homeostatic functions of the brain, it is certain that these cells are at least in part a cause of Alzheimer's disease. Historically, Alois Alzheimer himself has recognised this at the dawn of the disease description. However, the role of astroglia in this disease has been understudied. In this chapter, we summarise the various aspects of glial contribution to this disease and outline the potential of using these cells in prevention (exercise and environmental enrichment) and intervention of this devastating disease.

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“…Also, the classical "monoamine hypothesis of depression" says that the deficiency of NE is a culprit for the cognitive impairment [85]. NE/noradrenaline, the primary neurotransmitter released by the LC neurons targets the adrenergic receptors present on the microglia and astrocytes in the brain [86]. NE-activated ARs on glial cells stimulate the second messenger system and maintain the homeostasis in the brain.…”

Section: β2-adrenergic Receptors Agonists In Neuroprotectionmentioning

confidence: 99%

Adrenergic Receptors as Pharmacological Targets for Neuroinflammation and Neurodegeneration in Parkinson’s Disease

Sharma¹,

Flood²

2019

Neuroprotection

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Inflammation is a key component of the dopaminergic neurodegeneration seen in progressive Parkinson's disease (PD). The presence of activated glial cells, the participation of innate immune system, increased inflammatory molecules such as cytokines and chemokines, and increased oxidative stress and reactive oxygen species are the main neuroinflammatory characteristics present in progressive PD. Therapeutic targets which suppress pro-inflammatory responses by glial cells (mainly microglia) have been shown to be effective treatments for slowing or eliminating the progressive degeneration of neurons within the substantia nigra. In this chapter, we will detail a specific anti-inflammatory therapy using agonists to β2-adrenergic receptors that have been shown to be effective treatments for models of dopaminergic neurodegeneration and that have had efficacy in patients with progressive PD. We will also detail the possible molecular mechanisms of action of this therapeutic in stopping or reversing inflammation within the CNS.

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Preventing neurodegeneration by adrenergic astroglial excitation

Cited by 30 publications

References 132 publications

Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism

Astrocytes with TDP-43 inclusions exhibit reduced noradrenergic cAMP and Ca2+ signaling and dysregulated cell metabolism

Astroglia in Alzheimer’s Disease

Adrenergic Receptors as Pharmacological Targets for Neuroinflammation and Neurodegeneration in Parkinson’s Disease

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