Junxia X Tang

William Penn University, Filadelfia, Pennsylvania, United States

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Publications (12)59.12 Total impact

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    ABSTRACT: Post-mortem analysis has revealed reduced levels of the protein dysbindin in the brain of those suffering from the neurodevelopmental disorder schizophrenia. Consequently, mechanisms controlling the cellular levels of dysbindin and its interacting partners may participate in neurodevelopmental processes impaired in that disorder. To address this question, we studied loss-of-function mutations in the genes encoding dysbindin and its interacting BLOC-1 subunits. We focused on BLOC-1 mutants affecting synapse composition and function in addition to their established systemic pigmentation, hematological, and lung phenotypes. We tested phenotypic homogeneity and gene dosage effects in the mouse null alleles muted (Bloc1s5mu/mu) and dysbindin (Bloc1s8sdy/sdy). Transcripts of NMDA receptor subunits and GABAergic interneuron markers, as well as expression of BLOC-1 subunit gene products, were affected differently in the brains of Bloc1s5mu/mu and Bloc1s8sdy/sdy mice. Unlike Bloc1s8sdy/sdy, elimination of one or two copies of Bloc1s5 generated indistinguishable pallidin transcript phenotypes. We conclude that monogenic mutations abrogating the expression of a protein complex subunit differentially affect the expression of other complex transcripts and polypeptides as well as their downstream effectors. We propose that the genetic disruption of different subunits of protein complexes and combinations thereof diversifies phenotypic presentation of pathway deficiencies, contributing to the wide phenotypic spectrum and complexity of neurodevelopmental disorders.
    Journal of Biological Chemistry 04/2014; 289(20). DOI:10.1074/jbc.M114.553750 · 4.60 Impact Factor
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    ABSTRACT: OBJECTIVE:: Previous research suggests that a link between anesthetic exposure and Alzheimer disease exists. Because anesthetics are rarely given alone, we ask whether addition of surgery further modulates Alzheimer disease. BACKGROUND:: Cognitive dysfunction occurs after surgery in humans. Anesthesia alone produces cognitive decline in both older wild-type (WT) mice and rats, and the addition of surgery produces transient decline in young, adult WT mice. Because neuroinflammation has been implicated and occurs early in Alzheimer disease, we hypothesized that the neuroinflammatory stress associated with surgery would accelerate the progression of Alzheimer disease. METHODS:: Cecal ligation and excision were performed on presymptomatic 5- to 11-month-old triple-transgenic Alzheimer disease (3×TgAD) and C57BL/6 WT mice under desflurane anesthesia. Surgery animals were compared with aged-matched 3×TgAD and WT mice exposed to air or desflurane alone. Cognitive function was assessed via Morris water maze at 2 and 13 weeks postoperatively. Amyloid and tau pathology and inflammation and synaptic markers were quantified with immunohistochemistry, Luminex assay, enzyme-linked immunosorbent assay, or Western blot assays. RESULTS:: A significant cognitive impairment in 3×TgAD mice that underwent surgery compared with air or desflurane controls persisted to at least 14 weeks after surgery. Microglial activation, amyloidopathy, and tauopathy were enhanced by surgery as compared with desflurane alone. No differences between surgery, anesthetic, or air controls were detected in WT mice CONCLUSIONS:: Surgery causes a durable increment in Alzheimer pathogenesis, primarily through a transient activation of neuroinflammation.
    Annals of surgery 09/2012; 257(3). DOI:10.1097/SLA.0b013e318269d623 · 7.19 Impact Factor
  • Junxia X Tang, Maryellen F Eckenhoff
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    ABSTRACT: Research has improved the diagnosis of Alzheimer's disease, and at earlier stages, but effective therapy continues to be elusive. Current effort is focused on delay. Environmental factors are thought to interact with genetics to modulate the progression of the disease, and one such environmental factor is exposure to general anesthetics. The possibility that some anesthetic effects have long-term consequences is of general interest and concern. The difficulty of studying a chronic, age-related disease in humans combined with the fact that anesthetics are rarely given without surgery, has led to a focus on animal models. Transgenic mouse models have been developed to mimic the hallmarks of Alzheimer's disease, including amyloid beta accumulation (plaque), neurofibrillary tangles, and cognitive dysfunction. While none of the models recapitulate the human disease with high fidelity, they allow a first look at anesthetic-Alzheimer interactions in a reasonable time frame. In studies found to date, none have concluded that anesthetics alone cause a significant change in cognitive decline, but rather an acceleration in Alzheimer neuropathology. Further studies are required to define the best anesthetic paradigm for our elderly population to mitigate changes in neuropathology and potentially cognition.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 06/2012; DOI:10.1016/j.pnpbp.2012.06.007 · 4.03 Impact Factor
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    ABSTRACT: Carbon monoxide (CO) exposure at high concentrations results in overt neurotoxicity. Exposure to low CO concentrations occurs commonly yet is usually sub-clinical. Infants are uniquely vulnerable to a variety of toxins, however, the effects of postnatal sub-clinical CO exposure on the developing brain are unknown. Apoptosis occurs normally within the brain during development and is critical for synaptogenesis. Here we demonstrate that brief, postnatal sub-clinical CO exposure inhibits developmental neuroapoptosis resulting in impaired learning, memory, and social behavior. Three hour exposure to 5 ppm or 100 ppm CO impaired cytochrome c release, caspase-3 activation, and apoptosis in neocortex and hippocampus of 10 day old CD-1 mice. CO increased NeuN protein, neuronal numbers, and resulted in megalencephaly. CO-exposed mice demonstrated impaired memory and learning and reduced socialization following exposure. Thus, CO-mediated inhibition of neuroapoptosis might represent an important etiology of acquired neurocognitive impairment and behavioral disorders in children.
    PLoS ONE 02/2012; 7(2):e32029. DOI:10.1371/journal.pone.0032029 · 3.53 Impact Factor
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    ABSTRACT: The prevalence of postoperative cognitive disturbance, coupled with growing in vitro, cell, and animal evidence suggesting anesthetic effects on neurodegeneration, calls for additional study of the interaction between surgical care and Alzheimer neuropathology. The authors studied human cerebrospinal fluid (CSF) biomarkers during surgery. Eleven patients undergoing idiopathic nasal CSF leak correction were admitted to this Institutional Review Board-approved study. Lumbar subarachnoid catheters were placed before the procedure. Anesthesia was total intravenous propofol or remifentanil or inhalational sevoflurane, depending on provider choice. CSF samples were taken after catheter placement (base), at procedure end (0 h), and then at 6, 24, and 48 h. CSF was analyzed using xMAP Luminex immunoassay (Luminex, Austin, TX). Of the 11 patients (age range, 53 ± 6 yr), 8 were women; 4 received intravenous anesthesia, 6 sevoflurane, and 1 mixed. Procedures lasted 6.4 ± 2 h. Mean CSF amyloid-β(1-42) remained unchanged, but total-tau and phosphorylated-tau181P increased progressively until at least 48 h. Total-tau, phosphorylated-tau, or amyloid-β(1-42) concentrations were not different between anesthetic groups. CSF interleukin-10, S100Beta, and tumor necrosis factor α were increased similarly in both anesthetic groups at 24 h, but interleukin-6 was increased more in the inhalational group. These data indicate a robust neuroinflammatory response, including not only the usual markers (interleukin-6, tumor necrosis factor α, interleukin-10), but also S100Beta and tau, markers of injury. The total-tau/amyloid-β(1-42) ratio increased in a pattern consistent with Alzheimer disease, largely because of an increase in total-tau rather than a decline in amyloid-β(1-42). The differences in CSF interleukin-6 concentrations suggest that anesthetic management may make a difference in neuroinflammatory response.
    Anesthesiology 08/2011; 115(4):727-32. DOI:10.1097/ALN.0b013e31822e9306 · 6.17 Impact Factor
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    ABSTRACT: Experimental evidence suggests that anesthetics accelerate symptomatic neurodegenerative disorders such as Alzheimer's disease (AD). Because AD pathology precedes symptoms, we asked ourselves whether anesthetic exposure in the presymptomatic interval accelerated neuropathology and appearance of symptoms. Triple-transgenic AD mice were exposed to general aesthetics, either halothane or isoflurane, at 2, 4, and 6 months of age, they then underwent water maze cognitive testing 2 months later, and subsequently their brains were analyzed using enzyme-linked immunosorbent assay, immunoblots, and immunohistochemistry for amyloid and tau pathology and biomarkers. Learning and memory improved after halothane exposure in the 2-month-old group relative to controls, but no changes were noted in the isoflurane group. When gender was examined in all age groups, females exposed to halothane performed better as compared with those exposed to isoflurane or controls. Therefore, improvement in the 2-month exposure group is most likely because of a gender effect. Level of phospho-tau in the hippocampus was significantly increased 2 months after anesthesia, especially in the 6-month exposure group, but changes in amyloid, caspase, microglia, or synaptophysin levels were not detected. These results indicate that exposure to two different inhalation-type anesthetics during the presymptomatic phase of AD does not accelerate cognitive decline, after 2 months, and may cause a stress response, marked by hippocampal phosphorylated tau, resulting in preconditioning against the ongoing neuropathology, primarily in female mice.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 07/2011; 7(5):521-531.e1. DOI:10.1016/j.jalz.2010.10.003 · 17.47 Impact Factor
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    ABSTRACT: To summarize key studies and recent thought on the role of neuroinflammation in chronic neurodegeneration, and whether it can be modulated by anesthesia and surgery. A large and growing body of evidence shows that neuroinflammation participates in the development of neurodegeneration associated with Alzheimer's disease. Modulation may be possible early in the pathogenesis, and less so when cognitive symptoms appear. A dysfunctional hypoinflammatory response may permit accelerated damage due to other mechanisms in late disease. The peripheral inflammatory response elicited by surgery itself appears to provoke a muted neuroinflammatory response, which enhances ongoing neurodegeneration in some models. Anesthetics have both anti-inflammatory and proinflammatory effects depending on the drug and concentration, but in general, appear to play a small role in neuroinflammation. Human studies at the intersection of chronic neurodegeneration, neuroinflammation, and surgery/anesthesia are rare. The perioperative period has the potential to modulate the progression of chronic neurodegenerative diseases. The growing number of elderly having surgery, combined with the expanding life expectancy, indicates the potential for this interaction to have considerable public health implications, and call for further research, especially in humans.
    Current opinion in anaesthesiology 06/2011; 24(4):389-94. DOI:10.1097/ACO.0b013e32834871c5 · 2.53 Impact Factor
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    ABSTRACT: The perioperative period may have long-term consequences on cognitive function in the elderly patient. In this special article, we summarize the rationale and evidence that the anesthetic per se is a contributor. The evidence at this point is considered suggestive and further research is needed, especially in humans.
    Anesthesia and analgesia 10/2009; 110(2):421-6. DOI:10.1213/ANE.0b013e3181b80939 · 3.42 Impact Factor
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    ABSTRACT: DTNBP1 (dystrobrevin binding protein 1) remains a top candidate gene in schizophrenia. Reduced expression of this gene and of its encoded protein, dysbindin-1, have been reported in the brains of schizophrenia cases. It has not been established, however, if the protein reductions encompass all dysbindin-1 isoforms or if they are associated with decreased DTNBP1 gene expression. Using a matched pairs design in which each of 28 Caucasian schizophrenia cases was matched in age and sex to a normal Caucasian control, Western blotting of whole-tissue lysates of dorsolateral prefrontal cortex (DLPFC) revealed significant reductions in dysbindin-1C (but not in dysbindin-1A or -1B) in schizophrenia (P = 0.022). These reductions occurred without any significant change in levels of the encoding transcript in the same tissue samples and in the absence of the only DTNBP1 risk haplotype for schizophrenia reported in the USA. Indeed, no significant correlations were found between case-control differences in any dysbindin-1 isoform and the case-control differences in its encoding mRNA. Consequently, the mean 60% decrease in dysbindin-1C observed in 71% of our case-control pairs appears to reflect abnormalities in mRNA translation and/or processes promoting dysbindin-1C degradation (e.g. oxidative stress, phosphorylation and/or ubiquitination). Given the predominantly post-synaptic localization of dysbindin-1C and known post-synaptic effects of dysbindin-1 reductions in the rodent equivalent of the DLPFC, the present findings suggest that decreased dysbindin-1C in the DLPFC may contribute to the cognitive deficits of schizophrenia by promoting NMDA receptor hypofunction in fast-spiking interneurons.
    Human Molecular Genetics 08/2009; 18(20):3851-63. DOI:10.1093/hmg/ddp329 · 6.68 Impact Factor
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    ABSTRACT: Sandy mice have a deletion mutation in the gene encoding dysbindin-1, Dtnbp1, with consequent reduction of the protein in heterozygotes and its loss in homozygotes. The sandy mouse thus serves as an animal model of dysbindin-1 function. As this protein is concentrated in synaptic tissue and affects transmitter release, it may affect neuronal processes that mediate behavior. To investigate the neurobehavioral effects of the Dtnbp1 mutation, we studied littermate sandy and wild-type controls on a C57BL/6J genetic background. The three animal groups were indistinguishable in their external physical characteristics, sensorimotor skills and indices of anxiety-like behaviors. In the open field, however, homozygous animals were hyperactive and appeared to show less habituation to the initially novel environment. In the Morris water maze, homozygous animals displayed clear deficits in spatial learning and memory with marginal deficits in visual association learning. Apart from the last mentioned deficits, these abnormalities are consistent with hippocampal dysfunction and in some cases with elevated dopaminergic transmission via D2 dopamine receptors. As similar deficits in spatial learning and memory have been found in schizophrenia, where decreased dysbindin-1 has been found in the hippocampus, the sandy mouse may also model certain aspects of cognition and behavior relevant to schizophrenia.
    Genes Brain and Behavior 03/2009; 8(4):390-7. DOI:10.1111/j.1601-183X.2009.00477.x · 3.51 Impact Factor
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    ABSTRACT: Variation in the gene encoding dysbindin-1 (i.e., dystrobrevin-binding protein 1: DTNBP1) has frequently been associated with schizophrenia. Several studies have also found that dysbindin-1 gene and protein expression are altered in two affected brain areas in that disorder (i.e., the dorsolateral prefrontal cortex and the hippocampal formation). To provide the context and information needed for further study of these phenomena, this chapter provides the first comprehensive review of the dysbindin protein family. The family has three paralogs (dysbindin-1, -2, and -3), each of which is encoded by a different gene and expressed in more than one isoform. There are at least eight family members in humans (dysbindin-1A, -1B, -1C, -2A, -2B, -2C, -3A, and -3B). Dysbindin-1 is distinguished from other paralogs of the dysbindin family by the presence of a coiled coil domain important in interactions with other proteins. We focus on this paralog since it is the only one associated with schizophrenia thus far. Its gene, DTNBP1, has three major transcripts encoding isoforms running on western blots at approximately 50, 37, and 33 kDa (=dysbindin-1A, -1B, and -1C, respectively). The ∼37 kDa isoform cannot be studied in mice, which appear to lack an ortholog of human dysbindin-1B. While present in neuronal cell bodies throughout the central nervous system, dysbindin-1 is prominently enriched only in certain synaptic fields, mainly those known to be dopaminergic, glutamatergic, and/or GABAergic. In synaptic tissue of the human brain, dysbindin-1A is mainly concentrated in postsynaptic density fractions, dysbindin-1B in synaptic vesicle fractions, and dysbindin-1C in both those fractions. It is unknown if the isoforms differ in binding partners, but they are collectively known to bind a large number of proteins, including several proteins belonging to the biogenesis of lysosome-related organelles complex 1 (BLOC-1). An animal model of dysbindin-1’s functions is available in the sandy (sdy) mouse, which has a naturally occurring deletion mutation in DTNBP1 that leads to loss of dysbindin-1 in homozygous mice, which also shows a loss or reduction in other BLOC-1 binding partners. Among the many abnormalities of homozygous sdy mice are increased dopamine transmission in limbic tissue, decreased glutamate release and NMDA-mediated postsynaptic currents in prefrontal cortex, smaller excitatory evoked responses and loss of inhibitory responses after stimulation in the hippocampal formation, and severe deficits in spatial learning and memory processes. While the homozygous sdy mouse shares behavioral and biological features of schizophrenia, it is currently unclear if it serves an animal model of that disorder. It may, however, model cognitive aspects of schizophrenia. Dysbindin-1 may have diverse functions. Among these are the promotion of cell growth and proliferation, protection against neuronal apoptosis, facilitation of axon, dendrite, and dendritic spine growth, regulation of AP-3 cargo transport to lysosome-related organelles (including reserve pool synaptic vesicles), facilitation of glutamate release and inhibition of dopamine release, regulation of constitutive D2R cell surface expression, and promotion of cognitive processes. While the association between genetic variation in DTNBP1 and schizophrenia has been questioned recently, there is mounting evidence that the associations found reflect actual susceptibility variants in the gene. Even in the absence of such variants, altered dysbindin-1 gene and protein expression have been found in the dorsolateral prefrontal cortex and hippocampal formation of schizophrenia cases. These changes may contribute to the pathophysiology of the disorder by altering brain development, dopaminergic and glutamatergic transmission, functional connectivity of neuronal populations in the cerebral cortical and the hippocampal formation, and cognition.
    12/2008: pages 107-241;
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    ABSTRACT: DTNBP1 (dystrobrevin binding protein 1) remains one of the top candidate genes in schizophrenia. Reduced expression of this gene and the protein it encodes, dysbindin-1, has been reported in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia cases. It has not been established, however, if all dysbindin-1 isoforms are reduced in the DLPFC or if the reduction is associated with reduced DTNBP1 gene expression. Using Western blotting of whole-tissue lysates of the DLPFC with antibodies differentially sensitive to the three major isoforms of this protein (dysbindin-1A, -1B, and -1C), we found no significant differences between our schizophrenia cases and matched controls in dysbindin-1A or -1B, but did find a mean 46% reduction in dysbindin-1C in 71% of 28 case-control pairs (p = 0.022). This occurred in the absence of the one DTNBP1 risk haplotype for schizophrenia reported in the US and without alteration in levels of dysbindin-1C transcripts. Conversely, the absence of changes in the dysbindin-1A and -1B isoforms was accompanied by increased levels of their transcripts. We thus found no correspondence between alterations in dysbindin-1 gene and protein expression, the latter of which might be due to posttranslational modifications such as ubiquitination. Reduced DLPFC dysbindin-1C in schizophrenia probably occurs in PSDs, where we find dysbindin-1C to be heavily concentrated in the human brain. Given known postsynaptic effects of dysbindin-1 reductions in the rodent homolog of the prefrontal cortex, these findings suggest that reduced dysbindin-1C in the DLPFC may contribute to cognitive deficits of schizophrenia by promoting NMDA receptor hypofunction.

Publication Stats

228 Citations
59.12 Total Impact Points

Institutions

  • 2009–2014
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 2009–2012
    • University of Pennsylvania
      • • Department of Anesthesiology and Critical Care
      • • Center for Neurobiology and Behavior
      Filadelfia, Pennsylvania, United States