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BBA - Molecular Basis of Disease (v.1762, #6)

Editorial Board (pp. ii).

Anti-amyloidogenic effects of antioxidants: Implications for the prevention and therapeutics of Alzheimer's disease by Kenjiro Ono; Tsuyoshi Hamaguchi; Hironobu Naiki; Masahito Yamada (pp. 575-586).

Alzheimer's disease (AD) is one of the most common dementing disorders and has profound medical and social consequences. The initiating molecular event is unknown, and its pathophysiology is highly complex. However, free radical injury appears to be a fundamental process contributing to the neuronal death seen in this disorder, and many studies using surrogate markers of oxidative damage have provided evidence supporting this hypothesis. Various compounds with antioxidant ability attenuated the oxidative stress induced by amyloid β-protein (Aβ) in studies done in vitro and in vivo. Moreover, various antioxidants have been reported to inhibit the formation and extension of β-amyloid fibrils (fAβ), as well as to destabilize preformed fAβ in vitro. In cell culture experiments, destabilized fAβ were suggested to be less toxic than intact fAβ. In transgenic mice model studies, some antioxidant coumpounds reduced plaque burden in vivo. In this article, we review the recent advances in the research on the antioxidants that inhibit the formation of fAβ, as well as destabilize preformed fAβ. Although the mechanisms by which these compounds inhibit fAβ formation from Aβ, and destabilize preformed fAβ are still unclear, they could be key molecules for the development of preventives and therapeutics for AD.

Keywords: Alzheimer's disease; β-amyloid fibril; Antioxidant; Thioflavin T; Electron microscopy

Autoantibody biomarkers in the detection of cancer by Yoon S. Cho-Chung (pp. 587-591).

By definition, tumor biomarkers are selective molecules that can distinguish between patients with cancer and controls. Serum tumor markers have been the most widely used approach for cancer detection. However, the limitations of these markers, which are based on the measurement of tumor antigens, preclude their general use in cancer screening and diagnosis. Here we give an overview of recent cancer biomarker developments based on the detection of autoantibodies produced against tumor antigens in patients' sera. This new detection method can measure the autoantibodies for a spectrum of tumor antigens in a single assay, with sensitivity and specificity exceeding those obtained using the conventional antigen determination method. Autoantibodies against serum cancer biomarkers offer a novel technology for cancer detection.

Keywords: Autoantibody-based EIA; Cancer detection; Biomarkers; Autoantibody ECPKA; cAMP-dependent protein kinase

Acute effect of cigarette smoke on TNF-α release by macrophages mediated through the erk1/2 pathway by Loutfig Demirjian; Raja T. Abboud; Hong Li; Vincent Duronio (pp. 592-597).

Pulmonary emphysema is a major cause of mortality and morbidity in chronic obstructive pulmonary disease (COPD). Cigarette smoking is a major risk factor in the development of pulmonary emphysema. In this study, we investigated the acute effect of cigarette smoke in vitro on the production of tumour necrosis factor-α (TNF-α) using differentiated U937 cells, a macrophage model system. We found that stimulation of the macrophages with cigarette smoke media (CSM) leads to a rapid activation of extracellular-regulated kinases 1 and 2 (erk1/2), p90RSK and a transient decrease in phosphorylation of PKB/akt. The CSM also caused the subsequent induction of TNF-α release. Our studies revealed that U0126, an inhibitor of the erk1/2 pathway, markedly suppressed CSM-induced TNF-α release. Consistent with this finding, U0126 blocked CSM-stimulated erk1/2 phosphorylation, as well as phosphorylation of the downstream kinase, p90RSK. On the other hand, the PI3-K inhibitor, LY294002, and epidermal growth factor receptor (EGFR)-specific inhibitor, AG1478, did not suppress the release of TNF-α. Thus, CSM induction of TNF-α production by differentiated macrophages is regulated primarily via the erk1/2 pathway.

Keywords: Abbreviations; TNF-α; tumour necrosis factor-α; erk1/2; extracellular-regulated kinases 1 and 2; ELISA; enzyme linked immunosorbent assay; CSM; cigarette smoke mediaMacrophage; In vitro cigarette smoke exposure; Tumour necrosis factor-α; erk1/2

Abnormal glycosylation with hypersialylated O-glycans in patients with Sialuria by Suzan Wopereis; Umi M. Abd Hamid; Alison Critchley; Louise Royle; Raymond A. Dwek; Éva Morava; Jules G. Leroy; Bridget Wilcken; Aart J. Lagerwerf; Karin M.L.C. Huijben; Dirk J. Lefeber; Pauline M. Rudd; Ron A. Wevers (pp. 598-607).

Sialuria is an inborn error of metabolism characterized by coarse face, hepatomegaly and recurrent respiratory tract infections. The genetic defect in this disorder results in a loss of feedback control of UDP- N-acetylglucosamine 2-epimerase/ N-acetylmannosamine-kinase by CMP- N-acetylneuraminic acid (CMP-NeuAc) resulting in a substantial overproduction of cytoplasmic free sialic acid. This study addresses fibroblast CMP-NeuAc levels and N- and O-glycan sialylation of serum proteins from Sialuria patients. CMP-NeuAc levels were measured with HPLC in fibroblasts. Isoelectric focusing (IEF) of serum transferrin and of apolipoprotein C-III (apoC-III) was performed on serum of three Sialuria patients. Isoforms of these proteins can be used as specific markers for the biosynthesis of N- and core 1 O-glycans. Furthermore, total N- and O-linked glycans from serum proteins were analyzed by HPLC. HPLC showed a clear overproduction of CMP-NeuAc in fibroblasts of a Sialuria patient. Minor changes were found for serum N-glycans and hypersialylation was found for core 1 O-glycans on serum apoC-III and on total serum O-glycans in Sialuria patients. HPLC showed an increased ratio of disialylated over monosialylated core 1 O-glycans. The hypersialylation of core 1 O-glycans is due to the increase of NeuAcα2,6-containing structures (mainly NeuAcα2-3Galβ1-3[NeuAcα2-6]GalNAc). This may relate to K_M differences between GalNAc-α2,6-sialyltransferase and α2,3-sialyltransferases. This is the first study demonstrating that the genetic defect in Sialuria results in a CMP-NeuAc overproduction. Subsequently, increased amounts of α2,6-linked NeuAc were found on serum core 1 O-glycans from Sialuria patients. N-glycosylation of serum proteins seems largely unaffected. Sialuria is the first metabolic disorder presenting with hypersialylated O-glycans.

Keywords: Abbreviations; ApoC-III; apolipoproteinC-III; CDG; congenital disorders of glycosylation; CMP-NeuAc; cytidine 5′-monophospho-; N; -acetylneuraminic acid; Fuc; fucose; Gal; galactose; GalNAc; N; -acetylgalactosamine; GlcNAc; N; -acetylglucosamine; GNE/MNK; uridine 5'diphospho-; N; -acetylglucosamine-2-epimerase/; N; -acetylmannosamine kinase; GU; glucose units; IEF; isoelectric focusing; Man; mannose; ManNAc; N; -acetylmannosamine; NeuAc; N; -acetylneuraminic acid, sialic acid; NP-HPLC; normal phase HPLC; ST3Gal; CMP-; N; -acetylneuraminate-β-galactoside-α -2,3-sialyltransferase; ST6GalNAc; CMP-; N; -acetylneuraminate-α-; N; -acetylgalactosaminide-α-2,6-sialyltransferase; TEAA; triethylammonium acetate; TIEF; transferrin isoelectric focusing; UDP-GlcNAc; uridine 5'diphospho-; N; -acetylglucosamineCore I O-glycans; Hypersialylation; N-glycosylation; O-glycosylation, Sialuria OMIM 269921

Rapid pacing of embryoid bodies impairs mitochondrial ATP synthesis by a calcium-dependent mechanism—A model of in vitro differentiated cardiomyocytes to study molecular effects of tachycardia by Lorenz Schild; Alicja Bukowska; Andreas Gardemann; Pamela Polczyk; Gerburg Keilhoff; Michael Täger; Samuel C. Dudley; Helmut U. Klein; Andreas Goette; Uwe Lendeckel (pp. 608-615).

Tachycardia may cause substantial molecular and ultrastructural alterations in cardiac tissue. The underlying pathophysiology has not been fully explored. The purpose of this study was (I) to validate a three-dimensional in vitro pacing model, (II) to examine the effect of rapid pacing on mitochondrial function in intact cells, and (III) to evaluate the involvement of L-type-channel-mediated calcium influx in alterations of mitochondria in cardiomyocytes during rapid pacing. In vitro differentiated cardiomyocytes from P19 cells that formed embryoid bodies were paced for 24 h with 0.6 and 2.0 Hz. Pacing at 2.0 Hz increased mRNA expression and phosphorylation of ERK1/2 and caused cellular hypertrophy, indicated by increased protein/DNA ratio, and oxidative stress measured as loss of cellular thiols. Rapid pacing additionally provoked structural alterations of mitochondria. All these changes are known to occur in vivo during atrial fibrillation. The structural alterations of mitochondria were accompanied by limitation of ATP production as evidenced by decreased endogenous respiration in combination with decreased ATP levels in intact cells. Inhibition of calcium inward current with verapamil protected against hypertrophic response and oxidative stress. Verapamil ameliorated morphological changes and dysfunction of mitochondria. In conclusion, rapid pacing-dependent changes in calcium inward current via L-type channels mediate both oxidative stress and mitochondrial dysfunction. The in vitro pacing model presented here reflects changes occurring during tachycardia and, thus, allows functional analyses of the signaling pathways involved.

Keywords: Arrhythmia; Hypertrophy; Myocyte; Oxidative stress; Pacing; Mitochondria

Dose ranging and efficacy study of high-dose coenzyme Q₁₀ formulations in Huntington's disease mice by Karen M. Smith; Samantha Matson; Wayne R. Matson; Kerry Cormier; Steven J. Del Signore; Sean W. Hagerty; Edward C. Stack; Hoon Ryu; Robert J. Ferrante (pp. 616-626).

There is substantial evidence that a bioenergetic defect may play a role in the pathogenesis of Huntington's Disease (HD). A potential therapy for remediating defective energy metabolism is the mitochondrial cofactor, coenzyme Q₁₀ (CoQ₁₀). We have reported that CoQ₁₀ is neuroprotective in the R6/2 transgenic mouse model of HD. Based upon the encouraging results of the CARE-HD trial and recent evidence that high-dose CoQ₁₀ slows the progressive functional decline in Parkinson's disease, we performed a dose ranging study administering high levels of CoQ₁₀ from two commercial sources in R6/2 mice to determine enhanced efficacy. High dose CoQ₁₀ significantly extended survival in R6/2 mice, the degree of which was dose- and source-dependent. CoQ₁₀ resulted in a marked improvement in motor performance and grip strength, with a reduction in weight loss, brain atrophy, and huntingtin inclusions in treated R6/2 mice. Brain levels of CoQ₁₀ and CoQ₉ were significantly lower in R6/2 mice, in comparison to wild type littermate control mice. Oral administration of CoQ₁₀ elevated CoQ₁₀ plasma levels and significantly increased brain levels of CoQ₉, CoQ₁₀, and ATP in R6/2 mice, while reducing 8-hydroxy-2-deoxyguanosine concentrations, a marker of oxidative damage. We demonstrate that high-dose administration of CoQ₁₀ exerts a greater therapeutic benefit in a dose dependent manner in R6/2 mice than previously reported and suggest that clinical trials using high dose CoQ₁₀ in HD patients are warranted.

Keywords: Huntington's disease; Coenzyme Q; ₁₀; R6/2 transgenic mice; Therapy; ATP; 8-hydroxy-2-deoxyguanosine; Biomarkers

Effect of interferon alpha on MHC class II gene expression in ex vivo human islet tissue by Paul E. Harris; Donatella Malanga; Zhuoro Liu; Mark A. Hardy; Fabiola Souza; Giovanna Del Pozzo; Robert J. Winchester; Antonella Maffei (pp. 627-635).

Type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing β-cells of the islets of Langerhans. One still open question is where naive islet-reactive T cells encounter antigens and become stimulated. In this report we have re-examined the expression of MHC class II (MHCII) genes in human islets to further explore the possibility that non-professional antigen presenting cells (APCs) within islets contribute to autoimmunity. Since development of T1D has been linked to viral infections, we also studied ex-vivo MHCII expression in response to interferon-α (IFNα) in islet tissue and in different APCs. The findings are: first, MHCII genes expression in human islets is linked with the expression of the class II transactivator isoform transcribed from the promoter IV, similar to that described in non-professional APCs. Second, there is IFNα-mediated lineage-specific regulation of MHCII genes expression, seen as a decrease in the accumulation of MHCII transcripts in pancreatic islets opposite to an increase in dendritic cells and B-lymphoblastoid cell lines. Third, there is allele-specific regulation of the HLA-DQA1 gene by IFNα in islet tissue. These findings may begin to explain the molecular events that create favorable conditions for organ-specific autoimmunity and explain the incomplete penetrance of T1D susceptibility alleles.

Keywords: Human; Diabetes; MHC; Gene regulation; Interferon-α; Transplantation

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BBA - Molecular Basis of Disease (v.1762, #6)