科研之友
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摘要
Sporadic inclusion-body myositis (s-IBM) is the only muscle disease in which accumulation of amyloid-beta (A beta) in abnormal muscle fibers appears to play a key pathogenic role. Increased amyloid-beta precursor protein (A beta PP) and A beta accumulation have been reported to be upstream steps in the development of the s-IBM pathologic phenotype, based on cellular and animal models. A beta is released from A beta PP as a 40 or 42 aminoacid peptide. A beta 42 is considered more cytotoxic than A beta 40, 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 A beta 40 and A beta 42-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 A beta 42-immunoreactive inclusions, while only 69% of those fibers also contained A beta 40 deposits. By immuno-electronmicroscopy, A beta 42 was associated with 6-10 nm amyloid-like fibrils, small electron-dense floccular clumps and larger masses of amorphous material. A beta 40 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 A beta 42 was present in values 8.53-44.7 pg/ml, while A beta 40 was not detectable; normal age-matched control biopsies did not have any detectable A beta 42 or A beta 40. Thus, in s-IBM muscle fibers, A beta 42 is accumulated more than A beta 40. We suggest that A beta 42 oligomers and their cytotoxicity may play an important role in the s-IBM pathogenesis.
- 出版日期2009-5
