USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA, 90017, USA.
Abstract
Sporadic inclusion-body myositis (s-IBM) is the only muscle disease in which accumulation of amyloid-beta (Abeta) in abnormal muscle fibers appears to play a key pathogenic role. Increased amyloid-beta precursor protein (AbetaPP) and Abeta accumulation have been reported to be upstream steps in the development of the s-IBM pathologic phenotype, based on cellular and animal models. Abeta is released from AbetaPP as a 40 or 42 aminoacid peptide. Abeta42 is considered more cytotoxic than Abeta40, and it has a higher propensity to aggregate and form amyloid fibrils. Using highly specific antibodies, we evaluated in s-IBM muscle biopsies intra-muscle fiber accumulation of Abeta40 and Abeta42-immunoreactive aggregates by light- and electron-microscopic immunocytochemistry, and quantified their amounts by ELISA. In s-IBM, 80-90% of the vacuolated muscle fibers and 5-20% of the non-vacuolated muscle fibers contained plaque-like Abeta42-immunoreactive inclusions, while only 69% of those fibers also contained Abeta40 deposits. By immuno-electronmicroscopy, Abeta42 was associated with 6-10 nm amyloid-like fibrils, small electron-dense floccular clumps and larger masses of amorphous material. Abeta40 was present only on small patches of floccular clumps and amorphous material; it was not associated with 6-10 nm amyloid fibrils. By ELISA, in s-IBM muscle biopsies Abeta42 was present in values 8.53-44.7 pg/ml, while Abeta40 was not detectable; normal age-matched control biopsies did not have any detectable Abeta42 or Abeta40. Thus, in s-IBM muscle fibers, Abeta42 is accumulated more than Abeta40. We suggest that Abeta42 oligomers and their cytotoxicity may play an important role in the s-IBM pathogenesis.