Soluble macrophage factors trigger apoptosis in cultured hippocampal neurons

Flavin, Michael P.; Coughlin, Kevin; Ho, Lam T.

doi:10.1016/s0306-4522(97)00078-x

Cited by 66 publications

(44 citation statements)

References 46 publications

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“…It has been shown that cathepsin D level/expression is increased not only in neurons but also in activated microglia located in close proximity to neurons in vulnerable regions of NPC1 knock-out mouse brains (21, 24 -26, 30). Because microglia can play an active role in the loss of neurons (94,95), it is possible that enhanced levels of cathepsin D in microglia following its release into the extracellular milieu may contribute to the degeneration of neurons, as shown in our study. Alternatively, increased levels/activity of cathepsin D in the microglia may be involved in the removal of neuronal debris because this enzyme is capable of degrading microtubule-associated proteins (96) and myelin basic proteins (97).…”

Section: Discussionmentioning

confidence: 64%

Role of Cathepsin D in U18666A-induced Neuronal Cell Death

Amritraj

Wang

Revett

et al. 2013

Journal of Biological Chemistry

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Background: Cathepsin D has been implicated in Niemann-Pick type C (NPC) disease, which is associated with intracellular cholesterol accumulation. Results: Increased cytosolic and extracellular levels of cathepsin D enhanced neuronal death via different mechanisms. Conclusion: Leakage of cathepsin D within and outside the cell can cause cell death. Significance: Cathepsin D may be involved in the degeneration of neurons in NPC pathology.

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Section: Discussionmentioning

confidence: 64%

Role of Cathepsin D in U18666A-induced Neuronal Cell Death

Amritraj

Wang

Revett

et al. 2013

Journal of Biological Chemistry

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“…Nonetheless, CCR5 and CXCR4, as well as other chemokine receptors, are also present on neurons and astrocytes (12,(14)(15)(16)). Thus, a major question addressed in the present study is whether gp120-induced neuronal injury occurs as a consequence of direct interaction with neurons via chemokine receptors and their cognate G protein-signaling systems (13,17) or indirectly via the release of macrophage toxic factors, as previously suggested from in vitro experiments with gp120-conditioned medium after macrophage depletion (18)(19)(20)(21)(22). Finally, both direct and indirect pathways in conjunction could contribute to neuronal death, in a manner similar to that recently shown for the CXCR4-mediated killing of CD8 ϩ T cells (23).…”

mentioning

confidence: 87%

Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis

Kaul

Lipton

1999

Proc. Natl. Acad. Sci. U.S.A.

479

517

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HIV-1 glycoprotein gp120 induces injury and apoptosis in rodent and human neurons in vitro and in vivo and is therefore thought to contribute to HIV-associated dementia. In addition to CD4, different gp120 isolates bind to the ␣-or ␤-chemokine receptors CXCR4 and CCR5, respectively. These and other chemokine receptors are on brain macrophages/ microglia, astrocytes, and neurons. Thus, apoptosis could occur via direct interaction of gp120 with neurons, indirectly via stimulation of glia to release neurotoxic factors, or via both pathways. Here we show in rat cerebrocortical cultures that recapitulate the type and proportion of cells normally found in brain, i.e., neurons, astrocytes, and macrophages/ microglia, that the ␤-chemokines RANTES (regulated on activation, normal T cell expressed and secreted) and macrophage inf lammatory protein (MIP-1␤) protect neurons from gp120 SF2 -induced apoptosis. The gp120 SF2 isolate prefers binding to CXCR4 receptors, similar to the physiological ␣-chemokine ligands, stromal cell-derived factor (SDF)-1␣/␤. SDF-1␣/␤ failed to prevent gp120 SF2 neurotoxicity, and in fact also induced neuronal apoptosis. We could completely abrogate gp120 SF2 -induced neuronal apoptosis with the tripeptide TKP, which inhibits activation of macrophages/microglia. In contrast, TKP or depletion of macrophages/microglia did not prevent SDF-1 neurotoxicity. Inhibition of p38 mitogenactivated protein kinase ameliorated both gp120 SF2 -and SDF-1-induced neuronal apoptosis. Taken together, these results suggest that gp120 SF2 and SDF-1 differ in the cell type on which they stimulate CXCR4 to induce neuronal apoptosis, but both ligands use the p38 mitogen-activated protein kinase pathway for death signaling. Moreover, gp120 SF2 -induced neuronal apoptosis depends predominantly on an indirect pathway via activation of chemokine receptors on macrophages/microglia, whereas SDF-1 may act directly on neurons or astrocytes.

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“…Production of toxic products, inflammatory cytokines and chemokines in particular, is thought to be the predominant underlying mechanism. Activated microglial cells and macrophages can damage various cell types, including endothelial cells [25] , oligodendrocytes [68] , astrocytes [25] and neurons [69] , thereby contributing to injury. However, it is still controversial whether microglial activation is beneficial or detrimental after stroke [70,71] .…”

Section: Microglia and Macrophagesmentioning

confidence: 99%

Does Inflammation after Stroke Affect the Developing Brain Differently than Adult Brain?

2009

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The immature brain is prone to hypoxic-ischemic encephalopathy and stroke. The incidence of arterial stroke in newborns is similar to that in the elderly. However, the pathogenesis of ischemic brain injury is profoundly affected by age at the time of the insult. Necrosis is a dominant type of neuronal cell death in adult brain, whereas widespread neuronal apoptosis is unique for the early postnatal synaptogenesis period. The inflammatory response, in conjunction with excitotoxic and oxidative responses, is the major contributor to ischemic injury in both the immature and adult brain, but there are several areas where these responses diverge. We discuss the contribution of various inflammatory mechanisms to injury and repair after cerebral ischemia in the context of CNS immaturity. In particular, we discuss the role of lower expression of selectins, a more limited leukocyte transmigration, undeveloped complement pathways, a more rapid microglial activation, differences in cytokine and chemokine interplay, and a different threshold to oxidative stress in the immature brain. We also discuss differences in activation of intracellular pathways, especially nuclear factor κB and mitogen-activated protein kinases. Finally, we discuss emerging data on both the supportive and adverse roles of inflammation in plasticity and repair after stroke.

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Soluble macrophage factors trigger apoptosis in cultured hippocampal neurons

Cited by 66 publications

References 46 publications

Role of Cathepsin D in U18666A-induced Neuronal Cell Death

Role of Cathepsin D in U18666A-induced Neuronal Cell Death

Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis

Does Inflammation after Stroke Affect the Developing Brain Differently than Adult Brain?

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