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

Kang, Seong Su; Liu, Xia; Ahn, Eun Hee; Xiang, Jie; Manfredsson, Fredric P.; Yang, Xifei; Luo, Hongbo; Liles, L. Cameron; Weinshenker, David; Ye, Keqiang

doi:10.1172/jci130513

Cited by 73 publications

(72 citation statements)

References 48 publications

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“…Within suffering LC neurons, a compensatory LC hyperactivity can occur, which produces an increased ratio of NE turnover, which is reflected by intraneuronal increase in DOPEGAL/NE ratio and DOPEGAL production is associated with intense oxidative stress, which may contribute to neuronal death (Burke et al., 1999; Weinshenker, 2018). Kang et al, in large study in which they profited of different techniques, of different transgenic animals in vivo and different cell lines in vitro , showed that DOPEGAL might be key in triggering tau‐related LC modifications (Kang et al., 2020). In particular, they showed that: (a) DOPEGAL triggers, both in vivo and in vitro , the aggregation of Tau fibrils, (b) cell death‐induced by DOPEGAL requires the expression of Tau, (c) MAO‐A‐mediated DOPEGAL production within LC neurons activates the lysosomal enzyme asparagine endopeptidase (AEP), which mediates Tau cleavage in protein sites which favor its hyperphosphorylation and pathologic aggregation, (d) preventing DOPEGAL metabolism by aldehyde reductase inhibition is deleterious to the neuron.…”

Section: Evidence For Lc Degeneration In Admentioning

confidence: 99%

Locus Coeruleus and neurovascular unit: From its role in physiology to its potential role in Alzheimer’s disease pathogenesis

Giorgi

Galgani²,

Puglisi-Allegra

et al. 2020

J of Neuroscience Research

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Locus coeruleus (LC) is the main noradrenergic (NA) nucleus of the central nervous system. LC degenerates early during Alzheimer's disease (AD) and NA loss might concur to AD pathogenesis. Aside from neurons, LC terminals provide dense innervation of brain intraparenchymal arterioles/capillaries, and NA modulates astrocyte functions. The term neurovascular unit (NVU) defines the strict anatomical/functional interaction occurring between neurons, glial cells, and brain vessels. NVU plays a fundamental role in coupling the energy demand of activated brain regions with regional cerebral blood flow, it includes the blood-brain barrier (BBB), plays an active role in neuroinflammation, and participates also to the glymphatic system. NVU alteration is involved in AD pathophysiology through several mechanisms, mainly related to a relative oligoemia in activated brain regions and impairment of structural and functional BBB integrity, which contributes also to the intracerebral accumulation of insoluble amyloid. We review the existing data on the morphological features of LC-NA innervation of the NVU, as well as its contribution to neurovascular coupling and BBB proper functioning. After introducing the main experimental data linking LC with AD, which have repeatedly shown a key role of neuroinflammation and increased amyloid plaque formation, we discuss the potential mechanisms by which the loss of NVU modulation by LC might contribute to AD pathogenesis. Surprisingly, thus far not so many studies have tested directly these mechanisms in models of AD in which LC has been lesioned experimentally. Clarifying the interaction of LC with NVU in AD pathogenesis may disclose potential therapeutic targets for AD.

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Section: Evidence For Lc Degeneration In Admentioning

confidence: 99%

Locus Coeruleus and neurovascular unit: From its role in physiology to its potential role in Alzheimer’s disease pathogenesis

Giorgi

Galgani²,

Puglisi-Allegra

et al. 2020

J of Neuroscience Research

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“…Interestingly, although the LC develops pathology decades prior to clinical onset, it is relatively spared from degeneration until clinical presentation, which suggests that neuromelanin accumulation may work in concert with neuropathology to trigger neurodegeneration ( Weinshenker, 2018 ; Vila, 2019 ). Specifically, neuromelanin sequesters catecholamine metabolites, and the noradrenergic-specific metabolite DOPEGAL can trigger tau cleavage, hyperphosphorylation, and LC degeneration ( Weinshenker, 2018 ; Kang et al, 2020 ). Thus, accumulation and subsequent breakdown of neuromelanin granules during aging could potentially release large quantities of DOPEGAL, triggering tau pathology.…”

Section: Human Studiesmentioning

confidence: 99%

What’s That (Blue) Spot on my MRI? Multimodal Neuroimaging of the Locus Coeruleus in Neurodegenerative Disease

Kelberman

Keilholz

2020

Front. Neurosci.

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The locus coeruleus (LC) has long been underappreciated for its role in the pathophysiology of Alzheimer’s disease (AD), Parkinson’s disease (PD), and other neurodegenerative disorders. While AD and PD are distinct in clinical presentation, both are characterized by prodromal protein aggregation in the LC, late-stage degeneration of the LC, and comorbid conditions indicative of LC dysfunction. Many of these early studies were limited to post-mortem histological techniques due to the LC’s small size and location deep in the brainstem. Thus, there is a growing interest in utilizing in vivo imaging of the LC as a predictor of preclinical neurodegenerative processes and biomarker of disease progression. Simultaneously, neuroimaging in animal models of neurodegenerative disease holds promise for identifying early alterations to LC circuits, but has thus far been underutilized. While still in its infancy, a handful of studies have reported effects of single gene mutations and pathology on LC function in disease using various neuroimaging techniques. Furthermore, combining imaging and optogenetics or chemogenetics allows for interrogation of network connectivity in response to changes in LC activity. The purpose of this article is twofold: (1) to review what magnetic resonance imaging (MRI) and positron emission tomography (PET) have revealed about LC dysfunction in neurodegenerative disease and its potential as a biomarker in humans, and (2) to explore how animal models can be used to test hypotheses derived from clinical data and establish a mechanistic framework to inform LC-focused therapeutic interventions to alleviate symptoms and impede disease progression.

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“…Apart from amyloid pathology and neuroinflammation, LC degeneration has been shown to be strongly related to tau pathology; as abovementioned, the first signs of AD-related pathological alterations (years before the first clinical symptoms and the occurrence of amyloid plaques) occur in LC and are represented by the accumulation of pTAU (also denominated "pre-tangle Tau") [8]. Moreover, it has been observed that the NA metabolism by-product DOPEGAL, when produced in excess by NA neurons, is associated with tau aggregation [36], and that spreading of Tau pathology toward other brain structures might occur, at least in part, through LC efferents themselves [37]. Finally, it has been observed that LC lesion can worsen neurodegeneration and increase tau accumulation in AD transgenic mice [38].…”

Section: Potential Role Of Lc In the Pathophysiology In Neurodegeneramentioning

confidence: 97%

Locus Coeruleus Magnetic Resonance Imaging in Neurological Diseases

Galgani¹,

Lombardo

Latta

et al. 2020

Curr Neurol Neurosci Rep

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Purpose of Review Locus coeruleus (LC) is the main noradrenergic nucleus of the brain, and its degeneration is considered to be key in the pathogenesis of neurodegenerative diseases. In the last 15 years,MRI has been used to assess LC in vivo, both in healthy subjects and in patients suffering from neurological disorders. In this review, we summarize the main findings of LC-MRI studies, interpreting them in light of preclinical and histopathological data, and discussing its potential role as diagnostic and experimental tool. Recent findings LC-MRI findings were largely in agreement with neuropathological evidences; LC signal showed to be not significantly affected during normal aging and to correlate with cognitive performances. On the contrary, a marked reduction of LC signal was observed in patients suffering from neurodegenerative disorders, with specific features. Summary LC-MRI is a promising tool, which may be used in the future to explore LC pathophysiology as well as an early biomarker for degenerative diseases.

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

Cited by 73 publications

References 48 publications

Locus Coeruleus and neurovascular unit: From its role in physiology to its potential role in Alzheimer’s disease pathogenesis

Locus Coeruleus and neurovascular unit: From its role in physiology to its potential role in Alzheimer’s disease pathogenesis

What’s That (Blue) Spot on my MRI? Multimodal Neuroimaging of the Locus Coeruleus in Neurodegenerative Disease

Locus Coeruleus Magnetic Resonance Imaging in Neurological Diseases

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