Yang Wang

Case Western Reserve University, Cleveland, Ohio, United States

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Publications (10)49.94 Total impact

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    ABSTRACT: Intraneuronal amyloid-β (iAβ) accumulation has been demonstrated in Alzheimer disease (AD). Although extracellular amyloid plaques composed primarily of aggregated amyloid-β are one of the main pathological features of AD, functional characterization of iAβ is still lacking. In this study, we identified the normal distribution of iAβ through an analysis of hippocampal sections from a series of over 90 subjects with diverse antemortem clinical findings. In addition to AD cases, iAβ in pyramidal neurons was readily and reproducibly demonstrated in the majority of control cases. Similar findings for controls were made across all ages, spanning from infants to the elderly. There was no correlation of iAβ between gender, postmortem interval, or age. While the possible pathophysiological significance of iAβ accumulation in AD remains to be elucidated, careful examination of iAβ found in the normal brain may be informative for determining the biological role of iAβ and how this function changes during disease. Current findings support a physiological role for iAβ in neuronal function over the entire lifespan.
    No preview · Article · Mar 2014 · Current Alzheimer research
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    ABSTRACT: Oxidative stress is implicated as a pathogenic factor in a spectrum of chronic diseases, notably, neurodegenerative disease. Noteworthy in this regard is that type 1 diabetes mellitus (T1DM) results in oxidative stress, leading to systemic complications of T1DM. We hypothesized that oxidative stress associated with diabetic ketoacidosis (DKA) of T1DM might have measurable brain sequelae. Consistent with this hypothesis are neurohistology and neuroradiologic studies of T1DM that suggest oxidative insults are involved in the chronic complications of diabetic encephalopathy. To further address the role of oxidative stress in an acute setting, specifically in fatal brain edema (BE) associated with DKA, we studied neuronal localization and levels of oxidative stress markers reported to be increased in other neurodegenerative conditions. We demonstrated increased levels of 8-hydroxyguanosine (8OHG), 4-hydroxynonenal (HNE), and heme oxygenase-1 (HO-1) in the pyramidal neurons of the hippocampus of DKA BE in comparison to controls. However, in the cerebellum, only 8OHG was increased in the Purkinje cells and other cells of the molecular layer. These results indicate a role for oxidative stress in the pathogenesis of T1DM encephalopathy.
    Full-text · Article · Oct 2010 · Brain research
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    ABSTRACT: Mitochondrial dysfunction is a prominent feature of Alzheimer disease but the underlying mechanism is unclear. In this study, we investigated the effect of amyloid precursor protein (APP) and amyloid beta on mitochondrial dynamics in neurons. Confocal and electron microscopic analysis demonstrated that approximately 40% M17 cells overexpressing WT APP (APPwt M17 cells) and more than 80% M17 cells overexpressing APPswe mutant (APPswe M17 cells) displayed alterations in mitochondrial morphology and distribution. Specifically, mitochondria exhibited a fragmented structure and an abnormal distribution accumulating around the perinuclear area. These mitochondrial changes were abolished by treatment with beta-site APP-cleaving enzyme inhibitor IV. From a functional perspective, APP overexpression affected mitochondria at multiple levels, including elevating reactive oxygen species levels, decreasing mitochondrial membrane potential, and reducing ATP production, and also caused neuronal dysfunction such as differentiation deficiency upon retinoic acid treatment. At the molecular level, levels of dynamin-like protein 1 and OPA1 were significantly decreased whereas levels of Fis1 were significantly increased in APPwt and APPswe M17 cells. Notably, overexpression of dynamin-like protein 1 in these cells rescued the abnormal mitochondrial distribution and differentiation deficiency, but failed to rescue mitochondrial fragmentation and functional parameters, whereas overexpression of OPA1 rescued mitochondrial fragmentation and functional parameters, but failed to restore normal mitochondrial distribution. Overexpression of APP or Abeta-derived diffusible ligand treatment also led to mitochondrial fragmentation and reduced mitochondrial coverage in neuronal processes in differentiated primary hippocampal neurons. Based on these data, we concluded that APP, through amyloid beta production, causes an imbalance of mitochondrial fission/fusion that results in mitochondrial fragmentation and abnormal distribution, which contributes to mitochondrial and neuronal dysfunction.
    Full-text · Article · Jan 2009 · Proceedings of the National Academy of Sciences

  • No preview · Article · Jul 2008 · Alzheimer's and Dementia
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    ABSTRACT: Hibernating animals are very tolerant of trauma to the central nervous system such that dramatic fluctuations in cerebral blood flow occur during hibernation and arousal without apparent damage. Indeed, it was demonstrated that Arctic ground squirrels (AGS) experience acute and severe systemic hypoxia along with the dramatic fluctuation in cerebral blood flow when the animals are aroused from hibernation. While initial hypotheses concerned protective mechanisms in the hibernating state, recent evidence of sustained elevation of HIF1alpha in euthermic AGS from our laboratory suggests that a preparatory program of protective gene expression is chronically expressed in euthermic AGS. In this study we evaluated potential neuroprotective adaptations by examining the alteration of intracellular MAPK pathways that may be modulated by hypoperfusion/reperfusion in AGS during hibernation and arousal. We found that ERK and JNK are activated in both euthermic and aroused AGS compared to the hibernating group which positively correlated with HIF1alpha levels. The activation of ERK and JNK associated with HIF1alpha may play an important role in mediating neuroprotective adaptations that is essential for successful hibernation. Interestingly, p38 is activated in euthermic AGS but not in aroused AGS, which shows strong correlation with iNOS induction. Therefore, the attenuation of p38 activation and iNOS induction in hibernating and aroused animals may contribute to the attenuation of inflammation that plays important neuroprotective roles during hibernation. Taken together, the differential modulation of the MAPK pathways may be critical for neuroprotection of AGS necessary for fluctuations in oxygen and nutrient delivery during hibernation.
    No preview · Article · Jun 2005 · Journal of Neuroscience Research
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    ABSTRACT: Amyloid-beta is a leading candidate factor in the development of Alzheimer disease (AD), however the mechanisms involved are unclear. As such, there has been considerable interest in evidence showing that the neuronal damage caused by amyloid-beta is mediated by oxidative stress. Notably, oxidative stress leads to activation of stress-activated protein kinases, which we and others have shown are also involved in AD pathogenesis. One SAPK in particular, p38, appears to be crucial in AD and therefore, in the current study, we investigated the role of p38 activation in amyloid-beta cytotoxicity. Our data showed p38 activation was induced by amyloid-beta in a concentration-dependent manner in M17 human neuroblastoma cells. Notably, amyloid-beta toxicity was significantly decreased by inhibition of p38 activity by overexpressing dominant negative p38. Consistent with this, in primary cortical neurons amyloid-beta also induced p38 activation and amyloid-beta toxicity was significantly diminished when p38 was inhibited by its specific inhibitor, SB203580. Taken together, these data suggest that p38 is a key downstream effector of amyloid-beta-induced neuronal death and blocking this pathway may be of therapeutic value.
    No preview · Article · Jun 2005 · Neurochemical Research
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    ABSTRACT: While there is a host of pro-apoptotic stimuli that target neurons in Alzheimer disease (AD), given the chronicity of the disease and the survival of many neurons, those neurons must either avoid or, at minimum, delay apoptotic death signaling. In this study, we investigated Bcl-w, a novel member of the Bcl-2 family that promotes cell survival. In AD, we found increased levels of Bcl-w associated with neurofibrillary pathology and punctate intracytoplasmic structures whereas, in marked contrast, there are only low diffuse levels of Bcl-w in the neuronal cytoplasm of age-matched control cases. Immunoblot analysis confirmed that Bcl-w levels were significantly increased in AD. By electron microscopy, we determined that the increased Bcl-w expression in AD was ultrastructurally localized to mitochondria and neurofibrillary pathology. To investigate the cause and consequence of Bcl-w up-regulation in neurons, we found that fibrillized amyloid-beta led to increased Bcl-w protein levels in M17 human neuroblastoma cells, and that overexpression of Bcl-w significantly protected neurons against staurosporine- and amyloid-beta-induced apoptosis. Taken together, these series of results suggest that Bcl-w may play an important protective role in neurons in the diseased brain and that this aspect could be therapeutically harnessed to afford neuroprotection.
    Full-text · Article · Jul 2004 · Journal of Neurochemistry
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    Yang Wang · Pieter L deHaseth
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    ABSTRACT: The Escherichia coli transcription factor sigma 32 binds to core RNA polymerase to form the holoenzyme responsible for transcription initiation at heat shock promoters, utilized upon exposure of the cell to higher temperatures. We have developed two ways to assay sigma 32-dependent RNA synthesis in E. coli. The plasmid-borne reporter gene for both is lacZ (β-galactosidase), driven by the groE promoter. In one application, the cells are exposed to a temperature of 42°C in order to induce accumulation of endogenous sigma 32. The other involves isopropylthiogalactopyranoside (IPTG)-induced synthesis of sigma 32 at 30°C from a gene contained on a second plasmid. The latter employs DnaK− cells, which additionally contained a second mutation, inactivating the endogenous sigma 32 gene (Bukau and Walker, EMBO J. 9:4027-4036, 1990). These assays were used to delineate the sequences CTTGA (−37 to −33) and GNCCCCATNT (−18 to −9) as important for sigma 32 promoter activity. At each of the specified base pairs, substitutions were found which reduced promoter activity by greater than 75%. Activity was also dependent upon the number of base pairs separating the two regions.
    Full-text · Article · Nov 2003 · Journal of Bacteriology
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    ABSTRACT: JNK/SAPK has been implicated in the pathogenesis of Alzheimer's disease, but the upstream cascade leading to JNK/SAPK activation has not been elucidated in the disease. In this study, we focused on one of the physiological activators of JNK/SAPK, JNK kinase 1 (JKK1). Although there was no significant difference in the level and distribution of total JKK1 between Alzheimer's disease (AD) and age-matched control cases, increased levels of activated phospho-JKK1 were specifically localized to neurofibrillary pathology including neurofibrillary tangles, senile plaque neurites, granulovaualar degenerations and neuropil threads in severe AD (Braak stage V-VI), considerably overlapping with its downstream effector, phospho-JNK/SAPK, suggesting both a functional and mechanistic link. Nuclear localization of phospho-JKK1 was also found in mild (Braak stage III-IV) but not in severe AD cases (Braak stage V-VI), suggesting a possible re-distribution correlating with the progress of the disease. By immunoblot analyses, phospho-JKK1 was significantly increased in AD over control cases. Together, these findings lend further credence to the notion that the JNK/SAPK pathway is dysregulated in AD and also indicate an active role for this pathway in disease pathogenesis.
    Full-text · Article · May 2003 · Journal of Neurochemistry
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    ABSTRACT: Amino acid residues in region 2 of final sigma(70) have been shown to play an important role in the strand separation step that is necessary for formation of the functional or open RNA polymerase-promoter complex. Here we present a comparison of the roles of basic and aromatic amino acids in the accomplishment of this process, using RNA polymerase bearing alanine substitutions for both types of amino acids in region 2. We determined the effects of the substitutions on the kinetics of open complex formation, as well as on the ability of the RNA polymerase to form complexes with single-stranded DNA, and with forked DNA duplexes carrying a single-stranded overhang consisting of bases in the -10 region. We concluded that two basic amino acids (Lys(414) and Lys(418)) are important for promoter binding and demonstrated distinct roles, at a subsequent step, for two aromatic amino acids (Tyr(430) and Trp(433)). It is likely that these four amino acids, which are close to each other in the structure of final sigma(70), together are involved in the nucleation of the strand separation process.
    Full-text · Article · Sep 2001 · Journal of Biological Chemistry

Publication Stats

613 Citations
49.94 Total Impact Points


  • 2001-2014
    • Case Western Reserve University
      • • Department of Oral Pathology
      • • Department of Epidemiology and Biostatistics
      • • Institute of Pathology
      • • Department of Biochemistry
      Cleveland, Ohio, United States