Skip to main content

Advertisement

SpringerLink
Log in

Synaptic defects associated with s-inclusion body myositis are prevented by copper

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

Sporadic-inclusion body myositis (s-IBM) is the most common skeletal muscle disorder to afflict the elderly, and is clinically characterized by skeletal muscle degeneration. Its progressive course leads to muscle weakness and wasting, resulting in severe disability. The exact pathogenesis of this disease is unknown and no effective treatment has yet been found. An intriguing aspect of s-IBM is that it shares several molecular abnormalities with Alzheimer’s disease, including the accumulation of amyloid-β-peptide (Aβ). Both disorders affect homeostasis of the cytotoxic fragment Aβ1-42 during aging, but they are clinically distinct diseases. The use of animals that mimic some characteristics of a disease has become important in the search to elucidate the molecular mechanisms underlying the pathogenesis. With the aim of analyzing Aβ-induced pathology and evaluating the consequences of modulating Aβ aggregation, we used Caenorhabditis elegans that express the Aβ human peptide in muscle cells as a model of s-IBM. Previous studies indicate that copper treatment increases the number and size of amyloid deposits in muscle cells, and is able to ameliorate the motility impairments in Aβ transgenic C. elegans. Our recent studies show that neuromuscular synaptic transmission is defective in animals that express the Aβ-peptide and suggest a specific defect at the nicotine acetylcholine receptors level. Biochemical analyses show that copper treatment increases the number of amyloid deposits but decreases Aβ-oligomers. Copper treatment improves motility, synaptic structure and function. Our results suggest that Aβ-oligomers are the toxic Aβ species that trigger neuromuscular junction dysfunction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Adams RD, Kakulas BA, Samaha FA (1965) A myopathy with cellular inclusions. Trans Am Neurol Assoc 90:213–216

    PubMed  CAS  Google Scholar 

  • Askanas V, Engel WK (2001) Inclusion-body myositis: newest concepts of pathogenesis and relation to aging and Alzheimer disease. J Neuropathol Exp Neurol 60:1–14

    PubMed  CAS  Google Scholar 

  • Askanas V, Engel WK (2002) Inclusion-body myositis and myopathies: different etiologies, possibly similar pathogenic mechanisms. Curr Opin Neurol 15:525–531

    Article  PubMed  Google Scholar 

  • Askanas V, Engel WK (2006) Inclusion-body myositis: a myodegenerative conformational disorder associated with Abeta, protein misfolding, and proteasome inhibition. Neurology 66:S39–S48

    Article  PubMed  CAS  Google Scholar 

  • Askanas V, Engel WK (2007) Inclusion-body myositis, a multifactorial muscle disease associated with aging: current concepts of pathogenesis. Curr Opin Rheumatol 19:550–559

    Article  PubMed  Google Scholar 

  • 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 116:583–595

    Article  PubMed  Google Scholar 

  • Askanas V, Alvarez RB, Engel WK (1993) Beta-amyloid precursor epitopes in muscle fibers of inclusion body myositis. Ann Neurol 34:551–560

    Article  PubMed  CAS  Google Scholar 

  • Bayer TA, Schafer S, Simons A, Kemmling A, Kamer T, Tepest R, Eckert A, Schussel K, Eikenberg O, Sturchler-Pierrat C, Abramowski D, Staufenbiel M, Multhaup G (2003) Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice. Proc Natl Acad Sci USA 100:14187–14192

    Article  PubMed  CAS  Google Scholar 

  • Bellingham SA, Lahiri DK, Maloney B, La Fontaine S, Multhaup G, Camakaris J (2004) Copper depletion down-regulates expression of the Alzheimer’s disease amyloid-beta precursor protein gene. J Biol Chem 279:20378–20386

    Article  PubMed  CAS  Google Scholar 

  • Brenner S (1974) The genetics of Caenorhabditis elegans. Genetics 77:71–94

    PubMed  CAS  Google Scholar 

  • Buckingham SD, Jones AK, Brown LA, Sattelle DB (2009) Nicotinic acetylcholine receptor signalling: roles in Alzheimer’s disease and amyloid neuroprotection. Pharmacol Rev 61:39–61

    Article  PubMed  CAS  Google Scholar 

  • Bush AI, Pettingell WH Jr, Paradis MD, Tanzi RE (1994a) Modulation of A beta adhesiveness and secretase site cleavage by zinc. J Biol Chem 269:12152–12158

    PubMed  CAS  Google Scholar 

  • Bush AI, Pettingell WH, Multhaup G, d Paradis M, Vonsattel JP, Gusella JF, Beyreuther K, Masters CL, Tanzi RE (1994b) Rapid induction of Alzheimer A beta amyloid formation by zinc. Science 265:1464–1467

    Article  PubMed  CAS  Google Scholar 

  • Bush AI, Masters CL, Tanzi RE (2003) Copper, beta-amyloid, and Alzheimer’s disease: tapping a sensitive connection. Proc Natl Acad Sci USA 100:11193–11194

    Article  PubMed  CAS  Google Scholar 

  • Cerpa WF, Barria MI, Chacon MA, Suazo M, Gonzalez M, Opazo C, Bush AI, Inestrosa NC (2004) The N-terminal copper-binding domain of the amyloid precursor protein protects against Cu2+ neurotoxicity in vivo. FASEB J 18:1701–1703

    PubMed  CAS  Google Scholar 

  • Cerpa W, Varela-Nallar L, Reyes AE, Minniti AN, Inestrosa NC (2005) Is there a role for copper in neurodegenerative diseases? Mol Aspects Med 26:405–420

    Article  PubMed  CAS  Google Scholar 

  • Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y, Huang X, Goldstein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL, Bush AI (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 30:665–676

    Article  PubMed  CAS  Google Scholar 

  • D’Andrea MR, Nagele RG (2006) Targeting the alpha 7 nicotinic acetylcholine receptor to reduce amyloid accumulation in Alzheimer’s disease pyramidal neurons. Curr Pharm Des 12:677–684

    Article  PubMed  Google Scholar 

  • De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, Klein WL (2007) Abeta oligomers induce neuronal oxidative stress through an N-Methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem 282:11590–11601

    Article  PubMed  Google Scholar 

  • Dineley KT, Bell KA, Bui D, Sweatt JD (2002) Beta-amyloid peptide activates alpha 7 nicotinic acetylcholine receptors expressed in Xenopus oocytes. J Biol Chem 277:25056–25061

    Article  PubMed  CAS  Google Scholar 

  • Fay DS, Fluet A, Johnson CJ, Link CD (1998) In vivo aggregation of beta-amyloid peptide variants. J Neurochem 71:1616–1625

    Article  PubMed  CAS  Google Scholar 

  • Francis MM, Evans SP, Jensen M, Madsen DM, Mancuso J, Norman KR, Maricq AV (2005) The Ror receptor tyrosine kinase CAM-1 is required for ACR-16-mediated synaptic transmission at the C. elegans neuromuscular junction. Neuron 46:581–594

    Article  PubMed  CAS  Google Scholar 

  • Harrington AJ, Knight AL, Caldwell GA, Caldwell KA (2011) Caenorhabditis elegans as a model system for identifying effectors of alpha-synuclein misfolding and dopaminergic cell death associated with Parkinson’s disease. Methods 53:220–225

    Article  PubMed  CAS  Google Scholar 

  • Inestrosa NC, Cerpa W, Varela-Nallar L (2005) Copper brain homeostasis: role of amyloid precursor protein and prion protein. IUBMB Life 57:645–650

    Article  PubMed  CAS  Google Scholar 

  • Kessler H, Pajonk FG, Supprian T, Falkai P, Multhaup G, Bayer TA (2005) The role of copper in the pathophysiology of Alzheimer’s disease. Nervenarzt 76:581–585

    Article  PubMed  CAS  Google Scholar 

  • Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 27:796–807

    Article  PubMed  CAS  Google Scholar 

  • LaFerla FM, Oddo S (2005) Alzheimer’s disease: Abeta, tau and synaptic dysfunction. Trends Mol Med 11:170–176

    Article  PubMed  CAS  Google Scholar 

  • LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci 8:499–509

    Article  PubMed  CAS  Google Scholar 

  • Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440:352–357

    Article  PubMed  CAS  Google Scholar 

  • Link CD (1995) Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans. Proc Natl Acad Sci USA 92:9368–9372

    Article  PubMed  CAS  Google Scholar 

  • Link CD (2005) Invertebrate models of Alzheimer’s disease. Genes Brain Behav 4:147–156

    Article  PubMed  CAS  Google Scholar 

  • Link CD, Johnson CJ, Fonte V, Paupard M, Hall DH, Styren S, Mathis CA, Klunk WE (2001) Visualization of fibrillar amyloid deposits in living, transgenic Caenorhabditis elegans animals using the sensitive amyloid dye, X-34. Neurobiol Aging 22:217–226

    Article  PubMed  CAS  Google Scholar 

  • Lotz BP, Engel AG, Nishino H, Stevens JC, Litchy WJ (1989) Inclusion body myositis. Observations in 40 patients. Brain 112(Pt 3):727–747

    Article  PubMed  Google Scholar 

  • Masliah E, Mallory M, Alford M, DeTeresa R, Hansen LA, McKeel DW Jr, Morris JC (2001a) Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 56:127–129

    Article  PubMed  CAS  Google Scholar 

  • Masliah E, Alford M, Galasko D, Salmon D, Hansen LA, Good PF, Perl DP, Thal L (2001b) Cholinergic deficits in the brains of patients with parkinsonism-dementia complex of Guam. Neuroreport 12:3901–3903

    Article  PubMed  CAS  Google Scholar 

  • McColl G, Roberts BR, Gunn AP, Perez KA, Tew DJ, Masters CL, Barnham KJ, Cherny RA, Bush AI (2009) The Caenorhabditis elegans A beta 1-42 model of Alzheimer disease predominantly expresses A beta 3-42. J Biol Chem 284:22697–22702

    Article  PubMed  CAS  Google Scholar 

  • McFerrin J, Engel WK, Askanas V (1998) Impaired innervation of cultured human muscle overexpressing betaAPP experimentally and genetically: relevance to inclusion-body myopathies. Neuroreport 9:3201–3205

    Article  PubMed  CAS  Google Scholar 

  • Miller KG, Alfonso A, Nguyen M, Crowell JA, Johnson CD, Rand JB (1996) A genetic selection for Caenorhabditis elegans synaptic transmission mutants. Proc Natl Acad Sci USA 93:12593–12598

    Article  PubMed  CAS  Google Scholar 

  • Minniti AN, Rebolledo DL, Grez PM, Fadic R, Aldunate R, Volitakis I, Cherny RA, Opazo C, Masters C, Bush AI, Inestrosa NC (2009) Intracellular amyloid formation in muscle cells of Abeta-transgenic Caenorhabditis elegans: determinants and physiological role in copper detoxification. Mol Neurodegener 4:2

    Article  PubMed  Google Scholar 

  • Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L (2000) High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20:4050–4058

    PubMed  CAS  Google Scholar 

  • Nagele RG, D’Andrea MR, Anderson WJ, Wang HY (2002) Intracellular accumulation of beta-amyloid(1-42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer’s disease. Neuroscience 110:199–211

    Article  PubMed  CAS  Google Scholar 

  • Perry EK, Perry RH, Smith CJ, Dick DJ, Candy JM, Edwardson JA, Fairbairn A, Blessed G (1987) Nicotinic receptor abnormalities in Alzheimer’s and Parkinson’s diseases. J Neurol Neurosurg Psychiatry 50:806–809

    Article  PubMed  CAS  Google Scholar 

  • Perry EK, Morris CM, Court JA, Cheng A, Fairbairn AF, McKeith IG, Irving D, Brown A, Perry RH (1995) Alteration in nicotine binding sites in Parkinson’s disease, Lewy body dementia and Alzheimer’s disease: possible index of early neuropathology. Neuroscience 64:385–395

    Article  PubMed  CAS  Google Scholar 

  • Rebolledo DL, Minniti AN, Grez PM, Fadic R, Kohn R, Inestrosa NC (2008) Inclusion body myositis: a view from the Caenorhabditis elegans muscle. Mol Neurobiol 38:178–198

    Article  PubMed  CAS  Google Scholar 

  • Rebolledo DL, Aldunate R, Kohn R, Neira I, Minniti AN, Inestrosa NC (2011) Copper reduces Abeta oligomeric species and ameliorates neuromuscular synaptic defects in a C. elegans model of inclusion body myositis. J Neurosci 31:10149–10158

    Article  PubMed  CAS  Google Scholar 

  • Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, Kiers L, Cherny R, Li QX, Tammer A, Carrington D, Mavros C, Volitakis I, Xilinas M, Ames D, Davis S, Beyreuther K, Tanzi RE, Masters CL (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 60:1685–1691

    Article  PubMed  Google Scholar 

  • Sattelle DB, Buckingham SD (2006) Invertebrate studies and their ongoing contributions to neuroscience. Invert Neurosci 6:1–3

    Article  PubMed  Google Scholar 

  • Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791

    Article  PubMed  CAS  Google Scholar 

  • Strausak D, Mercer JF, Dieter HH, Stremmel W, Multhaup G (2001) Copper in disorders with neurological symptoms: Alzheimer’s, Menkes, and Wilson diseases. Brain Res Bull 55:175–185

    Article  PubMed  CAS  Google Scholar 

  • Toledo EM, Inestrosa NC (2009) Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1DeltaE9 mouse model of Alzheimer’s disease. Mol Psychiatry 15:272–285, 228

    Google Scholar 

  • Wang HY, Lee DH, Davis CB, Shank RP (2000a) Amyloid peptide Abeta(1-42) binds selectively and with picomolar affinity to alpha7 nicotinic acetylcholine receptors. J Neurochem 75:1155–1161

    Article  PubMed  CAS  Google Scholar 

  • Wang HY, Lee DH, D’Andrea MR, Peterson PA, Shank RP, Reitz AB (2000b) Beta-amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer’s disease pathology. J Biol Chem 275:5626–5632

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Paula Grez, for her contribution to Fig. 1 of this work, and Dr. William Klunk for providing the X-34 dye. We are grateful to Dr. Chris Link for his generous gift of C. elegans strains. Some strains were provided by the Caenorhabditis Genetics Center (CGC). Financial support: Grant 13980001, Centro de Envejecimiento y Regeneración (CARE), Programa de Financiamiento Basal 12/2007. FONDECYT 1120213 to RA.

Author information

Authors and Affiliations

  1. Center for Aging and Regeneration (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8370003, Santiago, Chile

    R. Aldunate, A. N. Minniti, D. Rebolledo & N. C. Inestrosa

  2. Escuela de Biotecnología, Facultad de Ciencias, Universidad Santo Tomás, Ejercito 146, Piso 6 Edif E, 8370003, Santiago, Chile

    R. Aldunate

Authors
  1. R. Aldunate
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. N. Minniti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Rebolledo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N. C. Inestrosa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. Aldunate.

Additional information

R. Aldunate and A. N. Minniti contributed equally to this study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (MP4 1120 kb)

Supplementary material 2 (MP4 178 kb)

Supplementary material 3 (MP4 405 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aldunate, R., Minniti, A.N., Rebolledo, D. et al. Synaptic defects associated with s-inclusion body myositis are prevented by copper. Biometals 25, 815–824 (2012). https://doi.org/10.1007/s10534-012-9553-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-012-9553-7

Keywords

Search

Navigation