, Volume 117, Issue 5, pp 569-574
Date: 12 Mar 2009

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

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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.

Supported by grants from the National Institutes of Health (Merit Award AG16768), the Muscular Dystrophy Association and The Myositis Association (to VA). FC is supported by the Fondation pour la Recherche Médicale.