Acta Neuropathologica

, Volume 120, Issue 5, pp 661–666 | Cite as

Novel demonstration of amyloid-β oligomers in sporadic inclusion-body myositis muscle fibers

  • Anna Nogalska
  • Carla D’Agostino
  • W. King Engel
  • William L. Klein
  • Valerie Askanas
Original Paper

Abstract

Accumulation of amyloid-β (Aβ) within muscle fibers has been considered an upstream step in the development of the s-IBM pathologic phenotype. Aβ42, which is considered more cytotoxic than Aβ40 and has a higher propensity to oligomerize, is preferentially increased in s-IBM muscle fibers. In Alzheimer disease (AD), low-molecular weight Aβ oligomers and toxic oligomers, also referred to as “Aβ-Derived Diffusible Ligands” (ADDLs), are considered strongly cytotoxic and proposed to play an important pathogenic role. ADDLs have been shown to be increased in AD brain. We now report for the first time that in s-IBM muscle biopsies Aβ-dimer, -trimer, and -tetramer are identifiable by immunoblots. While all the s-IBM samples we studied had Aβ-oligomers, their molecular weights and intensity varied between the patient samples. None of the control muscle biopsies had Aβ oligomers. Dot-immunoblots using highly specific anti-ADDL monoclonal antibodies also showed highly increased ADDLs in all s-IBM biopsies studied, while controls were negative. By immunofluorescence, in some of the abnormal s-IBM muscle fibers ADDLs were accumulated in the form of plaque-like inclusions, and were often increased diffusely in very small fibers. Normal and disease-controls were negative. By gold-immuno-electron microscopy, ADDL-immunoreactivities were in close proximity to 6–10 nm amyloid-like fibrils, and also were immunodecorating amorphous and floccular material. In cultured human muscle fibers, we found that inhibition of autophagy led to the accumulation of Aβ oligomers. This novel demonstration of Aβ42 oligomers in s-IBM muscle biopsy provides additional evidence that intra-muscle fiber accumulation of Aβ42 oligomers in s-IBM may contribute importantly to s-IBM pathogenic cascade.

Keywords

Sporadic inclusion-body myositis (s-IBM) Amyloid-β oligomers Amyloid-β derived diffusible ligands (ADDLs) Amyloid-β42 Amyloid β precursor protein (AβPP) Lysosomal inhibition Autophagy 

References

  1. 1.
    Askanas V, Engel WK (1992) Cultured normal and genetically abnormal human muscle. In: Rowland LP, Di Mauro S (eds) The handbook of clinical neurology, myopathies, vol 18. North Holland, Amsterdam, pp 85–116Google Scholar
  2. 2.
    Askanas V, Engel WK (2008) Inclusion-body myositis: muscle-fiber molecular pathology and possible pathogenic significance of its similarity to Alzheimer’s and Parkinson’s disease brains. Acta Neuropathol 116:583–595CrossRefPubMedGoogle Scholar
  3. 3.
    Askanas V, Engel WK, Nogalska A (2009) Inclusion-body myositis: a degenerative muscle disease associated with intra-muscle-fiber multiprotein aggregates, proteasome inhibition, endoplasmic reticulum stress, and decreased lysosomal degradation. Brain Pathol 19:493–506CrossRefPubMedGoogle Scholar
  4. 4.
    Askanas V, McFerrin J, Alvarez RB, Baque S, Engel WK (1997) Beta APP gene transfer into cultured human muscle induces inclusion-body myositis aspects. Neuroreport 8:2155–2158CrossRefPubMedGoogle Scholar
  5. 5.
    Askanas V, McFerrin J, Baque S, Alvarez RB, Sarkozi E, Engel WK (1996) Transfer of beta-amyloid precursor protein gene using adenovirus vector causes mitochondrial abnormalities in cultured normal human muscle. Proc Natl Acad Sci USA 93:1314–1319CrossRefPubMedGoogle Scholar
  6. 6.
    Barelli H, Lebeau A, Vizzavona J et al (1997) Characterization of new polyclonal antibodies specific for 40 and 42 amino acid-long amyloid beta peptides: their use to examine the cell biology of presenilins and the immunohistochemistry of sporadic Alzheimer’s disease and cerebral amyloid angiopathy cases. Mol Med 3:695–707PubMedGoogle Scholar
  7. 7.
    Chromy BA, Nowak RJ, Lambert MP et al (2003) Self-assembly of Abeta(1–42) into globular neurotoxins. Biochemistry 42:12749–12760CrossRefPubMedGoogle Scholar
  8. 8.
    Dalakas MC (2010) Inflammatory muscle diseases: a critical review on pathogenesis and therapies. Curr Opin Pharmacol. doi:10.1016/j.coph.2010.03.001
  9. 9.
    De Strooper B (2010) Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process. Physiol Rev 90:465–494CrossRefPubMedGoogle Scholar
  10. 10.
    El-Agnaf OM, Mahil DS, Patel BP, Austen BM (2000) Oligomerization and toxicity of beta-amyloid-42 implicated in Alzheimer’s disease. Biochem Biophys Res Commun 273:1003–1007CrossRefPubMedGoogle Scholar
  11. 11.
    Engel WK, Askanas V (2006) Inclusion-body myositis: clinical, diagnostic and pathologic aspects. Neurology 66:S20–S29CrossRefPubMedGoogle Scholar
  12. 12.
    Fratta P, Engel WK, McFerrin J, Davies KJ, Lin SW, Askanas V (2005) Proteasome inhibition and aggresome formation in sporadic inclusion-body myositis and in amyloid-{beta} precursor protein-overexpressing cultured human muscle fibers. Am J Pathol 167:517–526PubMedGoogle Scholar
  13. 13.
    Fukuchi K, Pham D, Hart M, Li L, Lindsey JR (1998) Amyloid beta deposition in skeletal muscle of transgenic mice: possible model of inclusion body myopathy. Am J Pathol 153:1687–1693PubMedGoogle Scholar
  14. 14.
    Gong Y, Chang L, Viola KL et al (2003) Alzheimer’s disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci USA 100:10417–10422CrossRefPubMedGoogle Scholar
  15. 15.
    Gouras GK, Tampellini D, Takahashi RH, Capetillo-Zarate E (2010) Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer’s disease. Acta Neuropathol 119:523–541CrossRefPubMedGoogle Scholar
  16. 16.
    Ikezoe K, Furuya H, Arahata H et al (2009) Amyloid-beta accumulation caused by chloroquine injections precedes ER stress and autophagosome formation in rat skeletal muscle. Acta Neuropathol 117:575–582CrossRefPubMedGoogle Scholar
  17. 17.
    Jin LW, Hearn MG, Ogburn CE et al (1998) Transgenic mice overexpressing the C-99 fragment of betaPP with an alpha-secretase site mutation develop a myopathy similar to human inclusion body myositis. Am J Pathol 153:1679–1686PubMedGoogle Scholar
  18. 18.
    Keller JN, Hanni KB, Markesbery WR (2000) Impaired proteasome function in Alzheimer’s disease. J Neurochem 75:436–439CrossRefPubMedGoogle Scholar
  19. 19.
    Kitazawa M, Green KN, Caccamo A, LaFerla FM (2006) Genetically augmenting Abeta42 levels in skeletal muscle exacerbates inclusion body myositis-like pathology and motor deficits in transgenic mice. Am J Pathol 168:1986–1997CrossRefPubMedGoogle Scholar
  20. 20.
    Kitazawa M, Vasilevko V, Cribbs DH, LaFerla FM (2008) Immunization with amyloid-beta attenuates inclusion body myositis-like myopathology and motor impairment in a transgenic mouse model. J Neurosci 29:6132–6141CrossRefGoogle Scholar
  21. 21.
    Klein WL, Stine WB, Teplow DB (2004) Small assemblies of unmodified amyloid beta-protein are the proximate neurotoxin in Alzheimer’s disease. Neurobiol Aging 25:569–580CrossRefPubMedGoogle Scholar
  22. 22.
    LaFerla FM, Green K, Oddo S (2007) Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci 8:499–509CrossRefPubMedGoogle Scholar
  23. 23.
    Lambert MP, Barlow AK, Chromy BA et al (1998) Diffusible, nonfibrillar ligands derived from Abeta1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95:6448–6453CrossRefPubMedGoogle Scholar
  24. 24.
    Lambert MP, Velasco PT, Chang L et al (2007) Monoclonal antibodies that target pathological assemblies of Abeta. J Neurochem 100:23–35CrossRefPubMedGoogle Scholar
  25. 25.
    Lindholm D, Wootz H, Korhonen L (2006) ER stress and neurodegenerative diseases. Cell Death Differ 13:385–392CrossRefPubMedGoogle Scholar
  26. 26.
    Mirabella M, Alvarez RB, Bilak M, Engel WK, Askanas V (1996) Difference in expression of phosphorylated tau epitopes between sporadic inclusion-body myositis and hereditary inclusion-body myopathies. J Neuropathol Exp Neurol 55:774–786CrossRefPubMedGoogle Scholar
  27. 27.
    Nixon RA (2007) Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci 120:4081–4091CrossRefPubMedGoogle Scholar
  28. 28.
    Nogalska A, D’Agostino C, Terracciano C, Engel WK, Askanas V (2009) p62/SQSTM1 is overexpressed and prominently accumulated in inclusions of sporadic inclusion-body myositis muscle fibers, and can help differentiating it from polymyositis and dermatomyositis. Acta Neuropathol 118:407–413CrossRefPubMedGoogle Scholar
  29. 29.
    Nogalska A, D’Agostino C, Terracciano C, Engel WK, Askanas V (2010) Impaired autophagy in sporadic inclusion-body myositis and in endoplasmic reticulum stress-provoked cultured human muscle fibers. Am J Pathol. doi:10.2353/ajpath.2010.100050
  30. 30.
    Nogalska A, Wojcik S, Engel WK, McFerrin J, Askanas V (2007) Endoplasmic reticulum stress induces myostatin precursor protein and NF-kappaB in cultured human muscle fibers: relevance to inclusion body myositis. Exp Neurol 204:610–618CrossRefPubMedGoogle Scholar
  31. 31.
    Oddo S, Caccamo A, Tran L et al (2006) Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem 281:1599–1604CrossRefPubMedGoogle Scholar
  32. 32.
    Shacka JJ, Klocke BJ, Shibata M et al (2006) Bafilomycin A1 inhibits chloroquine-induced death of cerebellar granule neurons. Mol Pharmacol 69:1125–1136CrossRefPubMedGoogle Scholar
  33. 33.
    Terracciano C, Nogalska A, Engel WK, Askanas V (2010) In AbetaPP-overexpressing cultured human muscle fibers proteasome inhibition enhances phosphorylation of AbetaPP751 and GSK3beta activation: effects mitigated by lithium and apparently relevant to sporadic inclusion-body myositis. J Neurochem 112:389–396CrossRefPubMedGoogle Scholar
  34. 34.
    Tomiyama T, Matsuyama S, Iso H et al (2010) A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci 30:4845–4856CrossRefPubMedGoogle Scholar
  35. 35.
    Tsuzuki K, Fukatsu R, Yoshida TakamaruY et al (1995) Amyloid beta protein in rat soleus muscle in chloroquine-induced myopathy using end-specific antibodies for A beta 40 and A beta 42: immunohistochemical evidence for amyloid beta protein. Neurosci Lett 202:77–80CrossRefPubMedGoogle Scholar
  36. 36.
    Vattemi G, Engel WK, McFerrin J, Askanas V (2004) Endoplasmic reticulum stress and unfolded protein response in inclusion body myositis muscle. Am J Pathol 164:1–7PubMedGoogle Scholar
  37. 37.
    Vattemi G, Nogalska A, Engel WK, D’Agostino C, Checler F, Askanas V (2009) Amyloid-beta42 is preferentially accumulated in muscle fibers of patients with sporadic inclusion-body myositis. Acta Neuropathol 117:569–574CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Anna Nogalska
    • 1
  • Carla D’Agostino
    • 1
  • W. King Engel
    • 1
  • William L. Klein
    • 2
  • Valerie Askanas
    • 1
  1. 1.Department of Neurology, USC Neuromuscular Center, Good Samaritan HospitalUniversity of Southern California Keck School of MedicineLos AngelesUSA
  2. 2.Department of Neurology and PhysiologyNorthwestern UniversityEvanstonUSA

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