Synapse Loss Induced by Interleukin-1β Requires Pre- and Post-synaptic Mechanisms

Mishra, Anjuli; Kim, Hee Jung; Shin, Angela H.; Thayer, Stanley A.

doi:10.1007/s11481-012-9342-7

Cited by 106 publications

(90 citation statements)

References 30 publications

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“…These results suggest that neuroinflammation may induce secondary event(s) for cognitive impairment to occur in a delayed phase. For example, incubation with IL-1β for 24 h induces synapse loss in rat hippocampal neuronal cultures (Mishra et al, 2012). Proinflammatory cytokines also reduce stimulation-induced brain derived neurotrophic factor production in rat hippocampus (Gonzalez et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Pyrrolidine dithiocarbamate attenuates surgery-induced neuroinflammation and cognitive dysfunction possibly via inhibition of nuclear factor κB

Zhang

Jiang²,

Zuo

2014

Neuroscience

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Surgery induces learning and memory impairment. Neuroinflammation may contribute to this impairment. Nuclear factor κB (NF-κB) is an important transcription factor to regulate the expression of inflammatory cytokines. We hypothesize that inhibition of NF-κB by pyrrolidine dithiocarbamate (PDTC) reduces neuroinflammation and the impairment of learning and memory. To test this hypothesis, four-month old male Fischer 344 rats were subjected to right carotid exploration under propofol and buprenorphine anesthesia. Some rats received two doses of 50 mg/kg PDTC given intraperitoneally 30 min before and 6 h after the surgery. Rats were tested in the Barnes maze and fear conditioning paradigm begun 6 days after the surgery. Expression of various proteins related to inflammation was examined in the hippocampus at 24 h or 21 days after the surgery. Here, surgery, but not anesthesia alone, had a significant effect on prolonging the time needed to identify the target hole during the training sessions of Barnes maze. Surgery also increased the time for identifying the target hole in the long-term memory test and decreased context-related learning and memory in fear conditioning test. Also, surgery increased nuclear expression of p65, a NF-κB component, decreased cytoplasmic amount of inhibitor of NF-κB, and increased the expression of interleukin-1β, interleukin-6, ionized calcium binding adaptor molecule 1 and active matrix metalloproteinase 9. Finally, surgery enhanced IgG extravasation in the hippocampus. These surgical effects were attenuated by PDTC. These results suggest that surgery, but not propofol-based anesthesia, induces neuroinflammation and impairment of learning and memory. PDTC attenuates these effects possibly by inhibiting NF-κB activation and the downstream matrix metalloproteinase 9 activity.

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Section: Discussionmentioning

confidence: 99%

Pyrrolidine dithiocarbamate attenuates surgery-induced neuroinflammation and cognitive dysfunction possibly via inhibition of nuclear factor κB

Zhang

Jiang²,

Zuo

2014

Neuroscience

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“…Syn-GFP expressed as distinct puncta that co-localized with immunoreactivity for the presynaptic marker protein Bassoon, indicating that Syn-GFP fluorescence was appropriately localized to presynaptic terminals. Furthermore, we have previously shown that Syn-GFP puncta responded to other stimuli such as IL-1β or lithium, treatments that induce decreases and increases in the number of postsynaptic densities, respectively (Kim and Thayer, 2009; Mishra et al, 2012). Therefore, Syn-GFP is a valid and responsive marker for presynaptic terminals and suitable for live cell imaging.…”

Section: Discussionmentioning

confidence: 99%

Human immunodeficiency virus-1 protein Tat induces excitotoxic loss of presynaptic terminals in hippocampal cultures

Shin

Thayer

2013

Molecular and Cellular Neuroscience

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Human Immunodeficiency Virus (HIV) infection of the CNS produces dendritic damage that correlates with cognitive decline in patients with HIV-associated neurocognitive disorders (HAND). HIV-induced neurotoxicity results in part from viral proteins shed from infected cells, including the HIV transactivator of transcription (Tat). We previously showed that Tat binds to the low density lipoprotein receptor-related protein (LRP), resulting in overactivation of NMDA receptors, activation of the ubiquitin-proteasome pathway, and subsequent loss of postsynaptic densities. Here, we show that Tat also induces a loss of presynaptic terminals. The number of presynaptic terminals was quantified using confocal imaging of synaptophysin fused to green fluorescent protein (Syn-GFP). Tat-induced loss of presynaptic terminals was secondary to excitatory postsynaptic mechanisms because treatment with an LRP antagonist or an NMDA receptor antagonist inhibited this loss. Treatment with nutlin-3, an E3 ligase inhibitor, prevented Tat-induced loss of presynaptic terminals. These data suggest that Tat-induced loss of presynaptic terminals is a consequence of excitotoxic postsynaptic activity. We previously found that ifenprodil, an NR2B subunit-selective NMDA receptor antagonist, induced recovery of postsynaptic densities. Here we show that Tat-induced loss of presynaptic terminals was reversed by ifenprodil treatment. Thus, Tat-induced loss of presynaptic terminals is reversible, and this recovery can be initiated by inhibiting a subset of postsynaptic NMDA receptors. Understanding the dynamics of synaptic changes in response to HIV infection of the CNS may lead to the design of improved pharmacotherapies for HAND patients.

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“…IL-1β exerts marked effects on neuronal function and survival. A recent study suggested that IL-1β reduces the number of synaptic connections by simultaneously activating multiple pathways that require both pre-and postsynaptic activity [32].…”

Section: Treatmentsmentioning

confidence: 99%

Stress Conditions Increase Vimentin Cleavage by Omi/HtrA2 Protease in Human Primary Neurons and Differentiated Neuroblastoma Cells

et al. 2014

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Dysfunctional Omi/HtrA2, a mitochondrial serine protease, has been implicated in various neurodegenerative disorders. Despite the wealth of evidence on the roles of Omi/HtrA2 in apoptosis, little is known about its cytosolic targets, the cleavage of which could account for the observed morphological changes such as cytoskeletal reorganizations in axons. By proteomic analysis, vimentin was identified as a substrate for Omi/HtrA2 and we have reported increased Omi/HtrA2 protease activity in Alzheimer disease (AD) brain. Here, we investigated a possible link between Omi/HtrA2 and vimentin cleavage, and consequence of this cleavage on mitochondrial distribution in neurons. In vitro protease assays showed vimentin to be cleaved by Omi/HtrA2 protease, and proximity ligation assay demonstrated an increased interaction between Omi/HtrA2 and vimentin in human primary neurons upon stress stimuli. Using differentiated neuroblastoma SH-SY5Y cells, we showed that Omi/HtrA2 under several different stress conditions induces cleavage of vimentin in wild-type as well as SH-SY5Y cells transfected with amyloid precursor protein with the Alzheimer disease-associated Swedish mutation. After stress treatment, inhibition of Omi/HtrA2 protease activity by the Omi/HtrA2 specific inhibitor, Ucf-101, reduced the cleavage of vimentin in wild-type cells. Following altered vimentin filaments integrity by stress stimuli, mitochondria was redistributed in differentiated SH-SY5Y cells and human primary neurons. In summary, the findings outlined in this paper suggest a role of Omi/HtrA2 in modulation of vimentin filamentous structure in neurons. Our results provide important findings for understanding the biological role of Omi/HtrA2 activity during stress conditions, and give knowledge of interplay between Omi/HtrA2 and vimentin which might affect mitochondrial distribution in neurons.

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Synapse Loss Induced by Interleukin-1β Requires Pre- and Post-synaptic Mechanisms

Cited by 106 publications

References 30 publications

Pyrrolidine dithiocarbamate attenuates surgery-induced neuroinflammation and cognitive dysfunction possibly via inhibition of nuclear factor κB

Pyrrolidine dithiocarbamate attenuates surgery-induced neuroinflammation and cognitive dysfunction possibly via inhibition of nuclear factor κB

Human immunodeficiency virus-1 protein Tat induces excitotoxic loss of presynaptic terminals in hippocampal cultures

Stress Conditions Increase Vimentin Cleavage by Omi/HtrA2 Protease in Human Primary Neurons and Differentiated Neuroblastoma Cells

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