tPA promotes ADAMTS-4-induced CSPG degradation, thereby enhancing neuroplasticity following spinal cord injury

Lemarchant, Sighild; Pruvost, Mathilde; Hébert, Marie; Gauberti, Maxime; Hommet, Yannick; Briens, Aurélien; Maubert, Eric; Gueye, Yatma; Féron, François; Petite, Didier; Mersel, Marcel; Rego, Jean–Claude do; Vaudry, Hubert; Koistinaho, Jari; Ali, Carine; Agin, Véronique; Emery, Évelyne; Vivien, Denis

doi:10.1016/j.nbd.2014.02.005

Cited by 44 publications

(49 citation statements)

References 55 publications

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“…Many other tPA substrates have been identified, including the GluN1 subunit of NMDA receptors (Nicole et al, 2001). tPA also has a wide range of other functions including activation of ADAMTS-4 to promote neuroplasticity (Lemarchant et al, 2014), conversion of pro-BDNF into BDNF to promote LTP in the hippocampus (Pang et al, 2004), and activation of PDGF-C (Fredriksson et al, 2004) to promote cell proliferation.…”

Section: Adaptation To Ischemiamentioning

confidence: 99%

Adaptive preconditioning in neurological diseases – therapeutic insights from proteostatic perturbations

et al. 2016

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In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a ‘proteostasis network’ and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge – the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson’s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain.

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Section: Adaptation To Ischemiamentioning

confidence: 99%

Adaptive preconditioning in neurological diseases – therapeutic insights from proteostatic perturbations

et al. 2016

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“…This hypothesis is comforted by previous reports showing the ability of rtPA to cleave/degrade CSPGs. 31, 32 Proteolytic cleavages of ColIV, ColXV and ColXVIII produce fragments with anti-angiogenic activities: arrestin, canstatin or tumstatin for ColIV, restin for ColXV and endostatin for ColXVIII. 33, 34 Increasing post-stroke repair constitutes one direction of interest to establish new effective therapies.…”

Section: Discussionmentioning

confidence: 99%

Lack of collagen XV is protective after ischemic stroke in mice

et al. 2017

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Collagens are key structural components of basement membranes, providing a scaffold for other components or adhering cells. Collagens and collagen-derived active fragments contribute to biological activities such as cell growth, differentiation and migration. Here, we report that collagen XV knock-out (ColXV KO) mice are resistant to experimental ischemic stroke. Interestingly, the infarcts of ColXV KO mice were as small as those of wild-type (WT) mice thrombolysed with recombinant tissue plasminogen activator (rtPA), the actual treatment for ischemic stroke. Importantly, there were no differences in the architecture of cerebrovascular anatomy between WT and ColXV KO mice. We found a twofold increase of the most potent pro-angiogenic factor, type A vascular growth endothelial factor (VEGF-A) in the ipsilateral cortex of rtPA-treated ischemic WT mice compared with untreated ischemic and sham-operated counterparts. A similar increase of VEGF-A was also found in both rtPA and untreated ischemic ColXV KO mice compared with sham ColXV KO mice. Finally, we evidenced that the levels of ColXV were increased in the plasma of WT mice treated with rtPA compared with untreated ischemic counterparts. Altogether, this study indicates that the lack ColXV is protective after stroke and that the degradation of endothelial ColXV may contribute to the beneficial effect of rtPA after ischemic stroke. The neuroprotection observed in ColXV KO mice may be attributed to the increased VEGF-A production following stroke in the ischemic territory.

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“…The expression of ADAMTS proteoglycanases was described to be modified in several CNS diseases or injuries (Cross et al, ; Demircan et al, ; Haddock, ; Lemarchant et al, ; Reid, ; Sasaki et al, ; Tauchi et al, ; Yuan et al, ; Zamanian et al, ), presumably due to a cytokine‐rich environment. For example, an increased astrocytic expression of ADAMTS‐4 was reported after transient middle cerebral artery occlusion (tMCAO) in the ipsilateral hemisphere at the mRNA and protein levels, respectively 6–24 h and 5 days post‐injury (Cross et al, ; Zamanian et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…So far, ADAMTS‐4 has been reported to be involved in the proteolysis of CSPGs (Lemarchant et al, ; Tauchi et al, a), the angiogenesis (Hsu et al, ), the synthesis/release of neurotrophic factors (Lemarchant et al, ), the differentiation of monocytes into macrophages and the invasion of macrophages (Ren et al, ). In this study, we pioneered in discovering that ADAMTS‐4 modulates neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Increasing evidence reveals that some ADAMTS proteoglycanases, for instance ADAMTS‐1 and −4, may play critical roles in the control of synaptic plasticity during CNS development and aging via both proteolytic‐dependent and ‐independent mechanisms (Hamel et al, ; Howell et al, ; Krstic et al, ). Additionally, ADAMTS‐4 has been previously described as a promising therapeutic strategy to improve axonal regeneration/collateral sprouting after spinal cord injury (SCI) in rats by degrading chondroitin sulfate proteoglycans (CSPGs) (Lemarchant et al, ; Tauchi et al, a). Conversely, ADAMTS‐4‐induced perineuronal net degradation promoted neurodegeneration and accelerated clinical signs of neuromuscular dysfunctions in a mouse model of amyotrophic lateral sclerosis (ALS) (Lemarchant et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Anti‐inflammatory effects of ADAMTS‐4 in a mouse model of ischemic stroke

Lemarchant

Dunghana

Pomeshchik

et al. 2016

Glia

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ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs type 4) is a metalloprotease capable to degrade chondroitin sulfate proteoglycans leading to cartilage destruction during arthritis or to neuroplasticity during spinal cord injury (SCI). Although ADAMTS-4 is an inflammatory-regulated enzyme, its role during inflammation has never been investigated. The aim of this study was to investigate the role of ADAMTS-4 in neuroinflammation. First, we evidenced an increase of ADAMTS-4 expression in the ischemic brain hemisphere of mouse and human patients suffering from ischemic stroke. Then, we described that ADAMTS-4 has predominantly an anti-inflammatory effect in the CNS. Treatment of primary microglia or astrocyte cultures with low doses of a human recombinant ADAMTS-4 prior to LPS exposure decreased NO production and the synthesis/release of pro-inflammatory cytokines including NOS2, CCL2, TNF-α, IL-1β and MMP-9. Accordingly, when cell cultures were transfected with silencing siRNA targeting ADAMTS-4 prior to LPS exposure, the production of NO and the synthesis/release of pro-inflammatory cytokines were increased. Finally, the feasibility of ADAMTS-4 to modulate neuroinflammation was investigated in vivo after permanent middle cerebral artery occlusion in mice. Although ADAMTS-4 treatment did not influence the lesion volume, it decreased astrogliosis and macrophage infiltration, and increased the number of microglia expressing arginase-1, a marker of alternatively activated cells with inflammation inhibiting functions. Additionally, ADAMTS-4 increased the production of IL-10 and IL-6 in the peri-ischemic area. By having anti-inflammatory and neuroregenerative roles, ADAMTS-4 may represent an interesting target to treat acute CNS injuries, such as ischemic stroke, SCI or traumatic brain injury. GLIA 2016;64:1492-1507.

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tPA promotes ADAMTS-4-induced CSPG degradation, thereby enhancing neuroplasticity following spinal cord injury

Cited by 44 publications

References 55 publications

Adaptive preconditioning in neurological diseases – therapeutic insights from proteostatic perturbations

Adaptive preconditioning in neurological diseases – therapeutic insights from proteostatic perturbations

Lack of collagen XV is protective after ischemic stroke in mice

Anti‐inflammatory effects of ADAMTS‐4 in a mouse model of ischemic stroke

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