Original Paper

Acta Neuropathologica

, Volume 117, Issue 5, pp 569-574

First online:

Amyloid-β42 is preferentially accumulated in muscle fibers of patients with sporadic inclusion-body myositis

  • Gaetano VattemiAffiliated withUSC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital
  • , Anna NogalskaAffiliated withUSC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital
  • , W. King EngelAffiliated withUSC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital
  • , Carla D’AgostinoAffiliated withUSC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital
  • , Frederic CheclerAffiliated withIPMC and IN2M, UMR6097 CNRS/UNSA, équipe labellisée “Fondation pour la Recherche Médicale”
  • , Valerie AskanasAffiliated withUSC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital Email author 

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Abstract

Sporadic inclusion-body myositis (s-IBM) is the only muscle disease in which accumulation of amyloid-β (Aβ) in abnormal muscle fibers appears to play a key pathogenic role. Increased amyloid-β precursor protein (AβPP) and Aβ accumulation have been reported to be upstream steps in the development of the s-IBM pathologic phenotype, based on cellular and animal models. Aβ is released from AβPP as a 40 or 42 aminoacid peptide. Aβ42 is considered more cytotoxic than Aβ40, 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 Aβ40 and Aβ42-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 Aβ42-immunoreactive inclusions, while only 69% of those fibers also contained Aβ40 deposits. By immuno-electronmicroscopy, Aβ42 was associated with 6–10 nm amyloid-like fibrils, small electron-dense floccular clumps and larger masses of amorphous material. Aβ40 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 Aβ42 was present in values 8.53-44.7 pg/ml, while Aβ40 was not detectable; normal age-matched control biopsies did not have any detectable Aβ42 or Aβ40. Thus, in s-IBM muscle fibers, Aβ42 is accumulated more than Aβ40. We suggest that Aβ42 oligomers and their cytotoxicity may play an important role in the s-IBM pathogenesis.

Keywords

Inclusion-body myositis Amyloid-β42 Amyloid-β40 Amyloid-β Amyloid-β oligomers Cytotoxicity