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Zhang, Can

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Zhang

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Can

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Zhang, Can
Author's Publications: search.filters.isAuthorOfPublication.0acacbe7-6562-446b-8949-6f5506dfc994

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    Cromolyn Reduces Levels of the Alzheimer’s Disease-Associated Amyloid β-Protein by Promoting Microglial Phagocytosis
    (Nature Publishing Group UK, 2018) Zhang, Can; Griciuc, Ana; Hudry, Eloise; Wan, Yu; Quinti, Luisa; Ward, Joseph; Forte, Angela M.; Shen, Xunuo; Ran, Chongzhao; Elmaleh, David; Tanzi, Rudolph
    Amyloid-beta protein (Aβ) deposition is a pathological hallmark of Alzheimer’s disease (AD). Aβ deposition triggers both pro-neuroinflammatory microglial activation and neurofibrillary tangle formation. Cromolyn sodium is an asthma therapeutic agent previously shown to reduce Aβ levels in transgenic AD mouse brains after one-week of treatment. Here, we further explored these effects as well as the mechanism of action of cromolyn, alone, and in combination with ibuprofen in APPSwedish-expressing Tg2576 mice. Mice were treated for 3 months starting at 5 months of age, when the earliest stages of β-amyloid deposition begin. Cromolyn, alone, or in combination with ibuprofen, almost completely abolished longer insoluble Aβ species, i.e. Aβ40 and Aβ42, but increased insoluble Aβ38 levels. In addition to its anti-aggregation effects on Aβ, cromolyn, alone, or plus ibuprofen, but not ibuprofen alone, increased microglial recruitment to, and phagocytosis of β-amyloid deposits in AD mice. Cromolyn also promoted Aβ42 uptake in microglial cell-based assays. Collectively, our data reveal robust effects of cromolyn, alone, or in combination with ibuprofen, in reducing aggregation-prone Aβ levels and inducing a neuroprotective microglial activation state favoring Aβ phagocytosis versus a pro-neuroinflammatory state. These findings support the use of cromolyn, alone, or with ibuprofen, as a potential AD therapeutic.
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    The double-edged role of copper in the fate of amyloid beta in the presence of anti-oxidants† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc01787a Click here for additional data file.
    (Royal Society of Chemistry, 2017) Yang, Jing; Zhang, Xueli; Zhu, Yiying; Lenczowski, Emily; Tian, Yanli; Yang, Jian; Zhang, Can; Hardt, Markus; Qiao, Chunhua; Tanzi, Rudolph; Moore, Anna; Ye, Hui; Ran, Chongzhao
    The biological fate of amyloid beta (Aβ) species is a fundamental question in Alzheimer’s disease (AD) pathogenesis. The competition between clearance and aggregation of Aβs is critical for the onset of AD. Copper has been widely considered to be an inducer of harmful crosslinking of Aβs, and an important triggering factor for the onset of AD. In this report, however, we present data to show that copper can also be an inducer of Aβ degradation in the presence of a large excess of well-known intrinsic (such as dopamine) or extrinsic (such as vitamin C) anti-oxidants. The degraded fragments were identified using SDS-Page gels, and validated via nanoLC-MS/MS. A tentative mechanism for the degradation was proposed and validated with model peptides. In addition, we performed electrophysiological analysis to investigate the synaptic functions in brain slices, and found that in the presence of a significant excess of vitamin C, Cu(ii) could prevent an Aβ-induced deficit in synaptic transmission in the hippocampus. Collectively, our evidence strongly indicated that a proper combination of copper and anti-oxidants might have a positive effect on the prevention of AD. This double-edged function of copper in AD has been largely overlooked in the past. We believe that our report is very important for fully understanding the function of copper in AD pathology.
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    Soluble Gamma-secretase Modulators Attenuate Alzheimer's β-amyloid Pathology and Induce Conformational Changes in Presenilin 1
    (Elsevier, 2017) Raven, Frank; Ward, Joseph F.; Zoltowska, Katarzyna; Wan, Yu; Bylykbashi, Enjana; Miller, Sean J.; Shen, Xunuo; Choi, Se Hoon; Rynearson, Kevin D.; Berezovska, Oksana; Wagner, Steven L.; Tanzi, Rudolph; Zhang, Can
    A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the Aβ42 peptide, which is generated from amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aβ42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of γ-secretase modulation remain largely unknown. Here, a representative of this SGSM scaffold, SGSM-36, was investigated using animals and cells expressing FAD mutations. SGSM-36 preferentially reduced Aβ42 levels without affecting either α- and β-secretase processing of APP nor Notch processing. Furthermore, an allosteric site was identified within the γ-secretase complex that allowed access of SGSM-36 using cell-based, fluorescence lifetime imaging microscopy analysis. Collectively, these studies provide mechanistic insights regarding SGSMs of this class and reinforce their therapeutic potential in AD.
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    A three-dimensional human neural cell culture model of Alzheimer’s disease
    (Nature Publishing Group, 2014) Choi, Se Hoon; Kim, Young Hye; Hebisch, Matthias; Sliwinski, Christopher; Lee, Seungkyu; D'Avanzo, Carla; Chen, Jennifer; Hooli, Basavaraj; Asselin, Caroline; Muffat, Julien; Klee, Justin B.; Zhang, Can; Wainger, Brian; Peitz, Michael; Kovacs, Dora; Woolf, Clifford; Wagner, Steven L.; Tanzi, Rudolph; Kim, Doo Yeon
    Alzheimer’s disease (AD) is the most common form of dementia, characterized by two pathological hallmarks: β-amyloid plaques and neurofibrillary tangles1. The amyloid hypothesis of AD posits that excessive accumulation of β-amyloid peptide (Aβ) leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau2,3. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. AD mouse models with familial AD (FAD) mutations exhibited Aβ-induced synaptic and memory deficits but they were not able to fully recapitulate other key pathological events of AD including clear neurofibrillary tangle pathology4,5. AD patient-derived human neurons showed elevated levels of toxic Aβ species and phosphor-tau (p-tau) but they also could not replicate β-amyloid plaques or neurofibrillary tangles6-11. Here we show that FAD mutations in the amyloid-β precursor protein (APP) and presenilin (PS) 1 genes are able to induce robust extracellular deposition of Aβ, including β-amyloid plaques, in a human neural stem cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of p-tau in the soma and neurites. Immunoelectron microscopy also demonstrated the presence of filamentous tau, only in detergent-resistant fractions from 3D-cultured cells expressing FAD mutations. Inhibition of Aβ generation with β- or γ-secretase inhibitors not only decreased Aβ pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated Aβ-mediated tau phosphorylation. In summary, we have successfully recapitulated Aβ and tau pathology in a single 3D human neural cell culture system for the first time. Our unique strategy for recapitulating AD pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models for other neurodegenerative disorders.
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    Higher intake of fruits, vegetables or their fiber reduces the risk of type 2 diabetes: A meta‐analysis
    (John Wiley and Sons Inc., 2015) Wang, Ping‐Yu; Fang, Jun‐Chao; Gao, Zong‐Hua; Zhang, Can; Xie, Shu‐Yang
    Abstract Aims/Introduction Some previous studies reported no significant association of consuming fruit or vegetables, or fruit and vegetables combined, with type 2 diabetes. Others reported that only a greater intake of green leafy vegetables reduced the risk of type 2 diabetes. To further investigate the relationship between them, we carried out a meta‐analysis to estimate the independent effects of the intake of fruit, vegetables and fiber on the risk of type 2 diabetes. Materials and Methods Searches of MEDLINE and EMBASE for reports of prospective cohort studies published from 1 January 1966 to 21 July 2014 were carried out, checking reference lists, hand‐searching journals and contacting experts. Results: The primary analysis included a total of 23 (11 + 12) articles. The pooled maximum‐adjusted relative risk of type 2 diabetes for the highest intake vs the lowest intake were 0.91 (95% confidence interval [CI] 0.87–0.96) for total fruits, 0.75 (95% CI 0.66–0.84) for blueberries, 0.87 (95% CI 0.81–0.93) for green leafy vegetables, 0.72 (95% CI 0.57–0.90) for yellow vegetables, 0.82 (95% CI 0.67–0.99) for cruciferous vegetables and 0.93 (95% CI 0.88–0.99) for fruit fiber in these high‐quality studies in which scores were seven or greater, and 0.87 (95% CI 0.80–0.94) for vegetable fiber in studies with a follow‐up period of 10 years or more. Conclusions: A higher intake of fruit, especially berries, and green leafy vegetables, yellow vegetables, cruciferous vegetables or their fiber is associated with a lower risk of type 2 diabetes.
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    Alterations of Serum Levels of BDNF-Related miRNAs in Patients with Depression
    (Public Library of Science, 2013) Li, You-Jie; Xu, Mei; Gao, Zong-Hua; Wang, Ya-Qi; Yue, Zhen; Zhang, Yan-Xia; Li, Xin-Xin; Zhang, Can; Xie, Shu-Yang; Wang, Ping-Yu
    Depression is a serious and potentially life-threatening mental disorder with unknown etiology. Emerging evidence shows that brain-derived neurotrophic factor (BDNF) and microRNAs (miRNAs) play critical roles in the etiology of depression. Here this study was aimed to identify and characterize the roles of BDNF and its putative regulatory miRNAs in depression. First, we identified that miR-182 may be a putative miRNA that regulates BDNF levels by bioinformatic studies, and characterized the effects of miR-182 on the BDNF levels using cell-based studies, side by side with miR-132 (a known miRNA that regulates BDNF expression). We showed that treatment of miR-132 and miR-182 respectively decreased the BDNF protein levels in a human neuronal cell model, supporting the regulatory roles of miR-132 and miR-182 on the BDNF expression. Furthermore, we explored the roles of miR-132 and miR-182 on the BDNF levels in depression using human subjects by assessing their serum levels. Compared with the healthy controls, patients with depression showed lower serum BDNF levels (via the enzyme-linked immunosorbent assays) and higher serum miR-132 and miR-182 levels (via the real-time PCR). Finally, the Pearson’s (or Spearman’s) correlation coefficient was calculated to study whether there was a relationship among the Self-Rating Depression Scale score, the serum BDNF levels, and serum BDNF-related miRNA levels. Our results revealed that there was a significant negative correlation between the SDS scores and the serum BDNF levels, and a positive correlation between the SDS scores and miR-132 levels. In addition, we found a reverse relationship between the serum BDNF levels and the miR-132/miR-182 levels in depression. Collectively, we provided evidence supporting that miR-182 is a putative BDNF-regulatory miRNA, and suggested that the serum BDNF and its related miRNAs may be utilized as important biomarkers in the diagnosis or as therapeutic targets of depression.
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    An AICD-based functional screen to identify APP metabolism regulators
    (BioMed Central, 2007) Zhang, Can; Khandelwal, Preeti J; Chakraborty, Ranjita; Cuellar, Trinna L; Sarangi, Srikant; Patel, Shyam A; Cosentino, Christopher P; O'Connor, Michael; Lee, Jeremy C; Tanzi, Rudolph; Saunders, Aleister J
    Background: A central event in Alzheimer's disease (AD) is the regulated intramembraneous proteolysis of the β-amyloid precursor protein (APP), to generate the β-amyloid (Aβ) peptide and the APP intracellular domain (AICD). Aβ is the major component of amyloid plaques and AICD displays transcriptional activation properties. We have taken advantage of AICD transactivation properties to develop a genetic screen to identify regulators of APP metabolism. This screen relies on an APP-Gal4 fusion protein, which upon normal proteolysis, produces AICD-Gal4. Production of AICD-Gal4 induces Gal4-UAS driven luciferase expression. Therefore, when regulators of APP metabolism are modulated, luciferase expression is altered. Results: To validate this experimental approach we modulated α-, β-, and γ-secretase levels and activities. Changes in AICD-Gal4 levels as measured by Western blot analysis were strongly and significantly correlated to the observed changes in AICD-Gal4 mediated luciferase activity. To determine if a known regulator of APP trafficking/maturation and Presenilin1 endoproteolysis could be detected using the AICD-Gal4 mediated luciferase assay, we knocked-down Ubiquilin 1 and observed decreased luciferase activity. We confirmed that Ubiquilin 1 modulated AICD-Gal4 levels by Western blot analysis and also observed that Ubiquilin 1 modulated total APP levels, the ratio of mature to immature APP, as well as PS1 endoproteolysis. Conclusion: Taken together, we have shown that this screen can identify known APP metabolism regulators that control proteolysis, intracellular trafficking, maturation and levels of APP and its proteolytic products. We demonstrate for the first time that Ubiquilin 1 regulates APP metabolism in the human neuroblastoma cell line, SH-SY5Y.