Thrombin induced inhibition of neurite outgrowth from dorsal root ganglion neurons

Gill, Jagjit S.; Pitts, Kelly R.; Rusnak, Frank; Owen, Whyte G.; Windebank, Anthony J.

doi:10.1016/s0006-8993(98)00344-8

Cited by 39 publications

(24 citation statements)

References 31 publications

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“…These include reversal of stellation of astrocytes (26, 81) and activation of microglia (29 -31, 82), perhaps to propagate proinflammatory responses and direct actions on neurons. Regarding the direct effects of thrombin on neurons, in vitro studies have shown that thrombin can induce rapid growth cone collapse, neurite retraction, and neuronal degeneration in neuroblastoma cells (83)(84)(85), motor (33,86), and sensory neurons (34,87). Curiously, hippocampal neurons were reported to be relatively more resistant to thrombin treatment (85,88).…”

Section: Discussionmentioning

confidence: 99%

“…These include astrocytic stellation and apoptosis (26 -28), microglial activation and proliferation (29 -31), as well as synaptic collapse, neuritic retraction, and apoptosis in motor and sensory neu-rons (32)(33)(34). In fact, thrombin is elevated (35,36), whereas the activity of the cognate thrombin inhibitor, protease nexin I, is sharply reduced (37,38) in AD brains, particularly around degenerating cerebral vessels (39 (31,40).…”

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confidence: 99%

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Rapid Tau Aggregation and Delayed Hippocampal Neuronal Death Induced by Persistent Thrombin Signaling

Suo

Citron

et al. 2003

Journal of Biological Chemistry

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Tau hyperphosphorylation, leading to self-aggregation, is widely held to underlie the neurofibrillary degeneration found in Alzheimer's disease (AD) and other tauopathies. However, it is unclear exactly what environmental factors may trigger this pathogenetic tau hyperphosphorylation. From several perspectives, the coagulation serine protease, thrombin, has been implicated in AD and activates several different protein kinase pathways but has not previously been shown how it may contribute to AD pathogenesis. Here we report that nanomolar thrombin induced rapid tau hyperphosphorylation and aggregation in murine hippocampal neurons via protease-activated receptors, which was followed by delayed synaptophysin reduction and apoptotic neuronal death. Mechanistic study revealed that a persistent thrombin signaling via protease-activated receptor 4 and prolonged downstream p44/42 mitogenactivated protein kinase activation are at least in part responsible. These results pathogenetically linked thrombin to subpopulations of AD and other tauopathies associated with cerebrovascular damage. Such knowledge may be instrumental in transforming therapeutic paradigms.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Rapid Tau Aggregation and Delayed Hippocampal Neuronal Death Induced by Persistent Thrombin Signaling

Suo

Citron

et al. 2003

Journal of Biological Chemistry

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“…Additionally, thrombin was present in the CSF of AD patients but not in that of controls (33). This is important, as thrombin can act as a neurotoxin by activating intracellular signaling cascades causing neurite retraction and stimulating apoptosis (34–36). Thrombin may also be influencing tau pathology, as treatment of immortalized hippocampal neuronal cells (HT22 cells) with thrombin resulted in the formation of thioflavin-S positive tau aggregates within 24 h, followed by an increase in cell death at 72 h (37).…”

Section: Tau Proteolysismentioning

confidence: 99%

Tau Clearance Mechanisms and Their Possible Role in the Pathogenesis of Alzheimer Disease

Chesser¹,

Pritchard²,

Johnson³

2013

Front. Neurol.

191

161

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One of the defining pathological features of Alzheimer disease (AD) is the intraneuronal accumulation of tau. The tau that forms these accumulations is altered both posttranslationally and conformationally, and there is now significant evidence that soluble forms of these modified tau species are the toxic entities rather than the insoluble neurofibrillary tangles. However there is still noteworthy debate concerning which specific pathological forms of tau are the contributors to neuronal dysfunction and death in AD. Given that increases in aberrant forms of tau play a role in the neurodegeneration process in AD, there is growing interest in understanding the degradative pathways that remove tau from the cell, and the selectivity of these different pathways for various forms of tau. Indeed, one can speculate that deficits in a pathway that selectively removes certain pathological forms of tau could play a pivotal role in AD. In this review we will discuss the different proteolytic and degradative machineries that may be involved in removing tau from the cell. How deficits in these different degradative pathways may contribute to abnormal accumulation of tau in AD will also be considered. In addition, the issue of the selective targeting of specific tau species to a given degradative pathway for clearance from the cell will be addressed.

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“…Recently, our understanding of the role of serine proteases such as thrombin, a key enzyme of the coagulation system, has been expanded to include actions in the nervous system (Gill et al, 1998). Thrombin affects protease-activated receptors (PARs), which are a family of G-protein-coupled receptors (Macfarlane et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Protease-Activated Receptor-1 and Platelet-Derived Growth Factor in Spinal Cord Neurons Are Implicated in Neuropathic Pain after Nerve Injury

Narita

Usui²,

Narita³

et al. 2005

J. Neurosci.

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Recently, it has been reported that both thrombin-sensitive protease-activated receptor 1 (PAR-1) and platelet-derived growth factor (PDGF) are present not only in platelets, but also in the CNS, which indicates that they have various physiological functions. In this study, we evaluated whether PAR-1/PDGF in the spinal cord could contribute to the development of a neuropathic pain-like state in mice. Thermal hyperalgesia and tactile allodynia induced by sciatic nerve ligation were significantly suppressed by repeated intrathecal injection of hirudin, which is characterized as a specific and potent thrombin inhibitor. Furthermore, a single intrathecal injection of thrombin produced long-lasting hyperalgesia and allodynia, and these effects were also inhibited by hirudin in normal mice. In nerveligated mice, the increase in the binding of

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Thrombin induced inhibition of neurite outgrowth from dorsal root ganglion neurons

Cited by 39 publications

References 31 publications

Rapid Tau Aggregation and Delayed Hippocampal Neuronal Death Induced by Persistent Thrombin Signaling

Rapid Tau Aggregation and Delayed Hippocampal Neuronal Death Induced by Persistent Thrombin Signaling

Tau Clearance Mechanisms and Their Possible Role in the Pathogenesis of Alzheimer Disease

Protease-Activated Receptor-1 and Platelet-Derived Growth Factor in Spinal Cord Neurons Are Implicated in Neuropathic Pain after Nerve Injury

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