Immunization with amyloid-beta attenuates inclusion body myositis-like myopathology and motor impairment in a transgenic mouse model.
Inclusion body myositis (IBM), the most common muscle disease to afflict the elderly, causes slow but progressive degeneration of skeletal muscle and ultimately paralysis. Hallmark pathological features include T-cell mediated inflammatory infiltrates and aberrant accumulations of proteins, including amyloid-beta (Abeta), tau, ubiquitinated-proteins, apolipoprotein E, and alpha-synuclein in skeletal muscle. A large body of work indicates that aberrant Abeta accumulation contributes to the myodegeneration. Here, we investigated whether active immunization to promote clearance of Abeta from affected skeletal muscle fibers mitigates the IBM-like myopathological features as well as motor impairment in a transgenic mouse model. We report that active immunization markedly reduces intracellular Abeta deposits and attenuates the motor impairment compared with untreated mice. Results from our current study indicate that Abeta oligomers contribute to the myopathy process as they were significantly reduced in the affected skeletal muscle from immunized mice. In addition, the anti-Abeta antibodies produced in the immunized mice blocked the toxicity of the Abeta oligomers in vitro, providing a possible key mechanism for the functional recovery. These findings provide support for the hypothesis that Abeta is one of the key pathogenic components in IBM pathology and subsequent skeletal muscle degeneration.
Kitazawa
Masashi
M
Department of Neurobiology and Behavior and Neurology, University of California, Irvine, California 92697-4545, USA.
Vasilevko
Vitaly
V
Cribbs
David H
DH
LaFerla
Frank M
FM
D016229:Amyloid beta-Peptides / Q000032:analysis / Q000276:immunology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000276:immunology; D016233:Immunotherapy, Active; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D009043:Motor Activity; D009069:Movement Disorders / Q000276:immunology / Q000628:therapy*; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000276:immunology*; D032446:Myoblasts; D018979:Myositis, Inclusion Body / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D010446:Peptide Fragments / Q000276:immunology; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D010446:Peptide Fragments; D058255:Protease Nexins; D011956:Receptors, Cell Surface