Norepinephrine provides short-term neuroprotection against Aβ1–42 by reducing oxidative stress independent of Nrf2 activation

Jhang, Kyoung A.; Lee, Eun Ok; Kim, Hye Sun; Chong, Young Hae

doi:10.1016/j.neurobiolaging.2014.05.020

Cited by 35 publications

(34 citation statements)

References 44 publications

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“…Approximately 15–25% of the neurons in the LC cultures were noradrenergic, as assessed by TH immunostaining (data not shown). Primary cortical neuron cultures were also made from TrkB F616A knock-in mice, as described [19]. …”

Section: Methodsmentioning

confidence: 99%

“…For example, β-adrenergic agonists have potent anti-inflammatory properties, can protect cultured neurons from Aβ toxicity, and enhance Aβ phagocytosis by microglia, while β-adrenergic antagonists have the opposite effects [12, 14–16]. However, in some cases, the ability of NE to protect cultured neurons from AD-related insults such as oxidative stress and Aβ cannot be fully mimicked by adrenergic agonists or blocked by adrenergic antagonists, suggesting the existence of non-canonical signaling mechanisms [16–19]. Moreover, the neuroprotective effects of NE have been assessed in hippocampal neurons, cortical neurons, and immortalized cell lines, but not LC neurons.…”

Section: Introductionmentioning

confidence: 99%

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Norepinephrine Protects against Amyloid-β Toxicity via TrkB

Liu

Weinshenker

2015

JAD

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The locus coeruleus (LC), the brainstem noradrenergic nucleus that is the sole source of norepinephrine (NE) in the forebrain, is one of the first structures affected in Alzheimer’s disease. Experimental ablation of the LC exacerbates, while increasing NE abates, AD-like neuropathology and cognitive deficits in animal models of the disease. Some neuroprotective effects of NE appear to be mediated by tropomyosin-related kinase B (TrkB), the canonical receptor for brain-derived neurotrophic factor (BDNF). Here, we report that NE dosedependently protected primary cortical and LC neurons from amyloid-β (Aβ) toxicity. The neuroprotective effects of NE were fully prevented by the Trk receptor antagonist K252a but only partially attenuated by adrenergic receptor antagonists and not mimicked by adrenergic agonists. Activation of TrkB by NE in cortical and LC neurons was confirmed by immunoblot and immunocytochemistry for phospho-TrkB. These results indicate that NE can activate TrkB and protect against Aβ toxicity, at least in part, via adrenergic receptor-independent mechanisms, and have implications for the consequences of LC degeneration in AD and potential therapies for the disease.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Norepinephrine Protects against Amyloid-β Toxicity via TrkB

Liu

Weinshenker

2015

JAD

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“…It has been proposed that the LC/NE system contributes to cognition through its role in promoting wakefulness and improving sensory signal detection that are necessary for navigating through and learning in a complex dynamic world [12, 13]. There is also clear evidence for a trophic and neuroprotective role for NE throughout the brain that limits neurodegenerative processes in cognitive and motor circuits and promotes hippocampal neurogenesis necessary for mnemonic processes [100, 101, 106, 120]. A greater appreciation for the precise way in which NE promotes cognition in the normal brain is crucial to developing a better understanding of how noradrenergic transmission goes awry in diverse neuropathologies such as AD, PD, ADHD, and SCZ (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…If loss of LC cells that innervate frontal cortical regions contributes to the impaired cognition and dementia seen in AD, then limiting their damage might help to prevent the development of these symptoms. Notably, NE has been shown to be neuroprotective by reducing oxidative stress [100]. Thus, the early loss of NE that would follow LC degeneration might exacerbate later cognitive decline by failing to limit frontal cortical cell death.…”

Section: Role Of Lc/ne System In Neuropathologiesmentioning

confidence: 99%

“…According to Braak staging [120], LC accumulates α -synuclein and degenerates prior to substantia nigra, which exacerbates degeneration of the nigrostriatal pathway due to loss of neuroprotective and trophic influences of NE [100]. The neuroprotective action of NE is evidenced by the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; a potent neurotoxin which destroys dopaminergic neurons) model of PD: compared to controls, mice with increased concentrations of NE in the central nervous system are less susceptible to neurotoxic effect of MPTP [121].…”

Section: Role Of Lc/ne System In Neuropathologiesmentioning

confidence: 99%

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Noradrenergic Modulation of Cognition in Health and Disease

2017

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Norepinephrine released by the locus coeruleus modulates cellular processes and synaptic transmission in the central nervous system through its actions at a number of pre- and postsynaptic receptors. This transmitter system facilitates sensory signal detection and promotes waking and arousal, processes which are necessary for navigating a complex and dynamic sensory environment. In addition to its effects on sensory processing and waking behavior, norepinephrine is now recognized as a contributor to various aspects of cognition, including attention, behavioral flexibility, working memory, and long-term mnemonic processes. Two areas of dense noradrenergic innervation, the prefrontal cortex and the hippocampus, are particularly important with regard to these functions. Due to its role in mediating normal cognitive function, it is reasonable to expect that noradrenergic transmission becomes dysfunctional in a number of neuropsychiatric and neurodegenerative diseases characterized by cognitive deficits. In this review, we summarize the unique role that norepinephrine plays in prefrontal cortical and hippocampal function and how its interaction with its various receptors contribute to cognitive behaviors. We further assess the changes that occur in the noradrenergic system in Alzheimer's disease, Parkinson's disease, attention-deficit/hyperactivity disorder, and schizophrenia and how these changes contribute to cognitive decline in these pathologies.

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Atrophy links lower novelty‐related locus coeruleus connectivity to cognitive decline in preclinical AD

Schneider,

Prokopiou,

Papp

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONAnimal research has shown that tau pathology in the locus coeruleus (LC) is associated with reduced norepinephrine signaling, lower projection density to the medial temporal lobe (MTL), atrophy, and cognitive impairment. We investigated the contribution of LC‐MTL functional connectivity (FCLC‐MTL) on cortical atrophy across Braak stage regions and its impact on cognition.METHODSWe analyzed functional magnetic resonance imaging and amyloid beta (Aβ) positron emission tomography data from 128 cognitively normal participants, associating novelty‐related FCLC‐MTL with longitudinal atrophy and cognition with and without Aβ moderation.RESULTSCross‐sectionally, lower FCLC‐MTL was associated with atrophy in Braak stage II regions. Longitudinally, atrophy in Braak stage 2 to 4 regions related to lower baseline FCLC‐MTL at elevated levels of Aβ, but not to other regions. Atrophy in Braak stage 2 regions mediated the relation between FCLC‐MTL and subsequent cognitive decline.DISCUSSIONFCLC‐MTL is implicated in Aβ‐related cortical atrophy, suggesting that LC‐MTL connectivity could confer neuroprotective effects in preclinical AD.Highlights Novelty‐related functional magnetic resonance imaging (fMRI) LC‐medial temporal lobe (MTL) connectivity links to longitudinal Aβ‐dependent atrophy. This relationship extended to higher Braak stage regions with increasing Aβ burden. Longitudinal MTL atrophy mediated the LC‐MTL connectivity–cognition relationship. Our findings mirror the animal data on MTL atrophy following NE signal dysfunction.

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Norepinephrine provides short-term neuroprotection against Aβ1–42 by reducing oxidative stress independent of Nrf2 activation

Cited by 35 publications

References 44 publications

Norepinephrine Protects against Amyloid-β Toxicity via TrkB

Norepinephrine Protects against Amyloid-β Toxicity via TrkB

Noradrenergic Modulation of Cognition in Health and Disease

Atrophy links lower novelty‐related locus coeruleus connectivity to cognitive decline in preclinical AD

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