Thrombin induces neurodegeneration and microglial activation in the cortex in vivo and in vitro: Proteolytic and non-proteolytic actions

Lee, Da Yong; Park, Keun Woo; Jin, Byung Kwan

doi:10.1016/j.bbrc.2006.05.174

Cited by 47 publications

(30 citation statements)

References 51 publications

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“…A number of studies, including ours, confirm the in vivo and in vitro neurotoxicity of thrombin on human fetal (42), dopaminergic (39,45), cortical (54), and hippocampal neurons (14,15,26). Importantly, thrombin is increased, whereas the activity of the thrombin inhibitor protease nexin I sharply reduced in the brain of AD patients (24,55,56).…”

Section: Discussionsupporting

confidence: 60%

IL-13-Induced Oxidative Stress via Microglial NADPH Oxidase Contributes to Death of Hippocampal Neurons In Vivo

Park

Baik

Jin

2009

The Journal of Immunology

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In the present study, we investigated the effects of IL-13, a well-known anti-inflammatory cytokine, on the thrombin-treated hippocampus in vivo. NeuN immunohistochemistry and Nissl staining revealed significant loss of hippocampal CA1 neurons upon intrahippocampal injection of thrombin. This neurotoxicity was accompanied by substantial microglial activation, as evident from OX-42 immunohistochemistry results. In parallel, Western blot analysis and hydroethidine histochemistry disclosed activation of NADPH oxidase, generation of reactive oxygen species, and oxidative damage in the hippocampal CA1 area showing hippocampal neuron degeneration. Interestingly, immunohistochemical and biochemical experiments showed that intrahippocampal injection of thrombin increased IL-13 immunoreactivity and IL-13 levels as early as 8 h after thrombin, reaching a peak at 7 days, which was maintained up to 14 days. Moreover, double-label immunohistochemistry revealed IL-13 immunoreactivity exclusively in activated microglia. IL-13-neutralizing Abs significantly rescued CA1 hippocampal neurons from thrombin neurotoxicity. In parallel, neutralization of IL-13 inhibited activation of NADPH oxidase, reactive oxygen species production, and oxidative damage. Additionally, IL-13 neutralization suppressed the expression of inducible NO synthase and several proinflammatory cytokines. To our knowledge, the present study is the first to show that IL-13 triggers microglial NADPH oxidase-derived oxidative stress, leading to the degeneration of hippocampal neurons in vivo, as occurs in cases of Alzheimer’s disease.

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Section: Discussionsupporting

confidence: 60%

IL-13-Induced Oxidative Stress via Microglial NADPH Oxidase Contributes to Death of Hippocampal Neurons In Vivo

Park

Baik

Jin

2009

The Journal of Immunology

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“…PAR1 contributes to post-stroke neurotoxicity [36], and PAR1 activation causes oligodendrocyte death [37], yet despite experimental data demonstrating thrombin as a neurotoxic agent [38], no trial to date has examined anti-thrombin receptor therapy as a potential treatment for neuroinflammatory-associated neurodegeneration. Several publications have demonstrated that aspirin, an agent that interferes with thrombin (the native agonist of PAR1) reduces fatigue in patients with MS [39, 40].…”

Section: Discussionmentioning

confidence: 99%

Protease-activated receptor-1 activation by granzyme B causes neurotoxicity that is augmented by interleukin-1β

Lee

Johnson

Gnanapavan

et al. 2017

J Neuroinflammation

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BackgroundThe cause of neurodegeneration in progressive forms of multiple sclerosis is unknown. We investigated the impact of specific neuroinflammatory markers on human neurons to identify potential therapeutic targets for neuroprotection against chronic inflammation.MethodsSurface immunocytochemistry directly visualized protease-activated receptor-1 (PAR1) and interleukin-1 (IL-1) receptors on neurons in human postmortem cortex in patients with and without neuroinflammatory lesions. Viability of cultured neurons was determined after exposure to cerebrospinal fluid from patients with progressive multiple sclerosis or purified granzyme B and IL-1β. Inhibitors of PAR1 activation and of PAR1-associated second messenger signaling were used to elucidate a mechanism of neurotoxicity.ResultsImmunohistochemistry of human post-mortem brain tissue demonstrated cells expressing higher amounts of PAR1 near and within subcortical lesions in patients with multiple sclerosis compared to control tissue. Human cerebrospinal fluid samples containing granzyme B and IL-1β were toxic to human neuronal cultures. Granzyme B was neurotoxic through activation of PAR1 and subsequently the phospholipase Cβ-IP3 second messenger system. Inhibition of PAR1 or IP3 prevented granzyme B toxicity. IL-1β enhanced granzyme B-mediated neurotoxicity by increasing PAR1 expression.ConclusionsNeurons within the inflamed central nervous system are imperiled because they express more PAR1 and are exposed to a neurotoxic combination of both granzyme B and IL-1β. The effects of these inflammatory mediators may be a contributing factor in the progressive brain atrophy associated with neuroinflammatory diseases. Knowledge of how exposure to IL-1β and granzyme B act synergistically to cause neuronal death yields potential novel neuroprotective treatments for neuroinflammatory diseases.

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“…The production of thrombin by endothelial cells in AD seems to be another proteomical dysfunction of these cells. This protein may be an interesting therapeutic target since thrombin in the brain parenchyma causes inflammation, abnormal angiogenesis, and activation of microglia and astrocytes [90,91]. In vivo, thrombin is known to increase Aβ production, induce tau hyperphosphorylation, and lead to cognitive impairment [92,93].…”

Section: Impairment Of Cerebral Microcirculation In Alzheimer's Diseasementioning

confidence: 99%

Dissecting the Contribution of Vascular Alterations and Aging to Alzheimer’s Disease

2015

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Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline that afflicts as many as 45 % of individuals who survive past the age of 85. AD has been associated with neurovascular dysfunction and brain accumulation of amyloid-β peptide, as well as tau phosphorylation and neurodegeneration, but the pathogenesis of the disease is still somewhat unclear. According to the amyloid cascade hypothesis of AD, accumulation of amyloid-β peptide (Aβ) aggregates initiates a sequence of events leading to neuronal injury and loss, and dementia. Alternatively, the vascular hypothesis of AD incorporates the vascular contribution to the disease, stating that a primary insult to brain microcirculation (e.g., stroke) not only contributes to amyloidopathy but initiates a non-amyloidogenic pathway of vascular-mediated neuronal dysfunction and injury, which involves blood-brain barrier compromise, with increased permeability of blood vessels, leakage of blood-borne components into the brain, and, consequently, neurotoxicity. Vascular dysfunction also includes a diminished brain capillary flow, causing multiple focal ischemic or hypoxic microinjuries, diminished amyloid-β clearance, and formation of neurotoxic oligomers, which lead to neuronal dysfunction. Here we present and discuss relevant findings on the contribution of vascular alterations during aging to AD, with the hope that a better understanding of the players in the "orchestra" of neurodegeneration will be useful in developing therapies to modulate the "symphony".

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Thrombin induces neurodegeneration and microglial activation in the cortex in vivo and in vitro: Proteolytic and non-proteolytic actions

Cited by 47 publications

References 51 publications

IL-13-Induced Oxidative Stress via Microglial NADPH Oxidase Contributes to Death of Hippocampal Neurons In Vivo

IL-13-Induced Oxidative Stress via Microglial NADPH Oxidase Contributes to Death of Hippocampal Neurons In Vivo

Protease-activated receptor-1 activation by granzyme B causes neurotoxicity that is augmented by interleukin-1β

Dissecting the Contribution of Vascular Alterations and Aging to Alzheimer’s Disease

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