Beta-amyloid is a substrate of autophagy in sporadic inclusion body myositis
Ann Neurol. 2007 May;61(5):476-83.
Authors/Editors: |
Lünemann JD Schmidt J Barthel K Wrede A Dalakas MC Münz C |
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Publication Date: | 2007 |
Type of Publication: | Journal Article |
METHODS: Colocalization of APP with the essential autophagy protein Atg8/LC3, which associates with preautophagosomal and autophagosomal membranes via lipidation, was analyzed in the CCL-136 muscle cell line and muscle biopsies by immunofluorescence. While APP was visualized with specific antibodies in the muscle cell line and in tissue sections. Atg8/LC3 localization was analyzed after GFP-Atg8/LC3 transfection or with an Atg8/LC3 specific antiserum, respectively.
RESULTS: We demonstrate here that Atg8/LC3 colocalizes with APP in cultured human muscle cells. In addition, APP/beta-amyloid-containing autophagosomes can be observed at increased frequency in muscle fibers of sIBM muscle biopsies, but not in non-myopathic muscle or non-vacuolated myopathic controls. APP/beta-amyloid and Atg8/LC3 double-positive compartments were almost exclusively observed in degenerating muscle fibers of the type II (fast-twitching) and were in part associated with overexpression of major histocompatibility complex (MHC) class I and II on myofibers and invasion by CD4(+) and CD8(+) cells.
INTERPRETATION: These findings indicate that APP/beta-amyloid is targeted for lysosomal degradation via macroautophagy and suggest that the autophagy pathway should be explored for its potential therapeutic merit in sIBM.