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      Interrelation of inflammation and APP in sIBM: IL-1β induces accumulation of β-amyloid in skeletal muscle

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          Abstract

          Distinct interrelationships between inflammation and β-amyloid-associated degeneration, the two major hallmarks of the skeletal muscle pathology in sporadic inclusion body myositis (sIBM), have remained elusive. Expression of markers relevant for these pathomechanisms were analysed in biopsies of sIBM, polymyositis (PM), dermatomyositis (DM), dystrophic and non-myopathic muscle as controls, and cultured human myotubes. By quantitative PCR, a higher upregulation was noted for the mRNA-expression of CXCL-9, CCL-3, CCL-4, IFN- γ, TNF-α and IL-1β in sIBM muscle compared to PM, DM and controls. All inflammatory myopathies displayed overexpression of degeneration-associated markers, yet only in sIBM, expression of the mRNA of amyloid precursor protein (APP) significantly and consistently correlated with inflammation in the muscle and mRNA-levels of chemokines and IFN- γ. Only in sIBM, immunohistochemical analysis revealed that inflammatory mediators including IL-1β co-localized to β-amyloid depositions within myofibres. In human myotubes, exposure to IL-1β caused upregulation of APP with subsequent intracellular aggregation of β-amyloid. Our data suggest that, in sIBM muscle, production of high amounts of pro-inflammatory mediators specifically induces β-amyloid-associated degeneration. The observations may help to design targeted treatment strategies for chronic inflammatory disorders of the skeletal muscle.

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          Most cited references 37

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          TNF-alpha acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle.

          Atrogin1/MAFbx is an ubiquitin ligase that mediates muscle atrophy in a variety of catabolic states. We recently found that H2O2 stimulates atrogin1/MAFbx gene expression. Since the cytokine tumor necrosis factor-alpha (TNF-alpha) stimulates both reactive oxygen production and general activity of the ubiquitin conjugating pathway, we hypothesized that TNF-alpha would also increase atrogin1/MAFbx gene expression. As with H2O2, we found that TNF-alpha exposure up-regulates atrogin1/MAFbx mRNA within 2 h in C2C12 myotubes. Intraperitoneal injection of TNF-alpha increased atrogin1/MAFbx mRNA in skeletal muscle of adult mice within 4 h. Exposing myotubes to either TNF-alpha or H2O2 also produced general activation of the mitogen-activated protein kinases (MAPKs): p38, ERK1/2, and JNK. The increase in atrogin1/MAFbx gene expression induced by TNF-alpha was not altered significantly by ERK inhibitor PD98059 or the JNK inhibitor SP600125. In contrast, atrogin1/MAFbx up-regulation and the associated increase in ubiquitin conjugating activity were both blunted by p38 inhibitors, either SB203580 or curcumin. These data suggest that TNF-alpha acts via p38 to increase atrogin1/MAFbx gene expression in skeletal muscle.
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            Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease.

            C1q, the recognition component of the classical complement activation pathway, is a multifunctional protein known to be expressed in brain of Alzheimer's disease (AD) patients. To experimentally address the role of C1q in AD, a mouse model lacking C1q (APPQ-/-) was generated by crossing Tg2576 animals (APP) with C1q-deficient mice. The pathology of APPQ-/- was compared with that of APP mice and B6SJL controls at 3-16 months of age by immunohistochemistry and Western blot analysis. At younger ages (3-6 months), when no plaque pathology was present, no significant differences were seen in any of the neuronal or glial markers tested. At older ages (9-16 months), the APP and APPQ-/- mice developed comparable total amyloid and fibrillar beta-amyloid in frontal cortex and hippocampus; however, the level of activated glia surrounding the plaques was significantly lower in the APPQ-/- mice at 12 and 16 months. In addition, although Tg2576 mice showed a progressive decrease in synaptophysin and MAP2 in the CA3 area of hippocampus compared with control B6SJL at 9, 12, and 16 months, the APPQ-/- mice had significantly less of a decrease in these markers at 12 and 16 months. In a second murine model for AD containing transgenes for both APP and mutant presenilin 1 (APP/PS1), a similar reduction of pathology was seen in the APPPS1Q-/- mice. These data suggest that at ages when the fibrillar plaque pathology is present, C1q exerts a detrimental effect on neuronal integrity, most likely through the activation of the classical complement cascade and the enhancement of inflammation.
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              Sporadic inclusion body myositis--diagnosis, pathogenesis and therapeutic strategies.

              Sporadic inclusion body myositis (sIBM) presents with a characteristic clinical phenotype of slow-onset weakness and atrophy, affecting proximal and distal limb muscles and facial and pharyngeal muscles. Histologically, sIBM is characterized by chronic myopathic features, lymphocytic infiltrates invading non-vacuolated fibers, vacuolar degeneration, and accumulation of amyloid-related proteins. The cause of sIBM is unclear, but two processes-one autoimmune and the other degenerative-appear to occur in parallel. In contrast to dystrophies, in sIBM the autoinvasive CD8(+) T cells are cytotoxic and antigen-driven, invading muscle fibers expressing major histocompatibility complex class I antigen and costimulatory molecules. The concurrent degenerative features include vacuolization, filamentous inclusions and intracellular accumulations of amyloid-beta-related molecules. Although viruses have not been amplified from the muscle fibers, at least 12 cases of sIBM have been seen in association with retroviral infections, indicating that a chronic persistent viral infection might be a potential triggering factor. Emerging data imply that continuous upregulation of cytokines and major histocompatibility complex class I on the muscle fibers causes an endoplasmic reticulum stress response, resulting in intracellular accumulation of misfolded glycoproteins and activation of the transcription factor NFkappaB, leading to further cytokine activation. In spite of the brisk, antigen-driven T-cell infiltrates, sIBM does not respond to immunotherapies. New therapies using monoclonal antibodies against lymphocyte signaling pathways might prove helpful in arresting disease progression.
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                Author and article information

                Journal
                Brain
                brainj
                brain
                Brain
                Oxford University Press
                0006-8950
                1460-2156
                May 2008
                17 April 2008
                17 April 2008
                : 131
                : 5
                : 1228-1240
                Affiliations
                1Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA, 2Department of Neurology and Department of Experimental and Clinical Neuroimmunology, 3Department of Neuropathology, University of Göttingen, Germany and 4Neuromuscular Division, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA
                Author notes
                Correspondence to: Dr Jens Schmidt, Department of Neurology and Department of Experimental and Clinical Neuroimmunology, University of Göttingen, Waldweg 33, 37073 Göttingen, Germany, or Dr Marinos Dalakas, Neuromuscular Division, Thomas Jefferson University, 900 Walnut Street, Suite 200, Philadelphia, PA 19107, USA E-mail: j.schmidt@ 123456gmx.org or marinos.dalakas@ 123456jefferson.edu
                Article
                awn053
                10.1093/brain/awn053
                2367696
                18420712
                Published by Oxford University Press on behalf of the Guarantors of Brain (2008).

                The online version of this article has been published under an open access model. users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commerical purposes provided that: the original authorship is properly and fully attributed; the Journal and the Guarantors of Brain are attributed as the original place of publication with the correction citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

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