Article

Genetically augmenting Abeta42 levels in skeletal muscle exacerbates inclusion body myositis-like pathology and motor deficits in transgenic mice.

Department of Neurobiology and Behavior, 1109 Gillespie Neuroscience Facility, University of California, Irvine, Irvine, CA 92697-4545, USA.
American Journal Of Pathology (Impact Factor: 4.6). 07/2006; 168(6):1986-97. DOI: 10.2353/ajpath.2006.051232
Source: PubMed

ABSTRACT The pathogenic basis of inclusion body myositis (IBM), the leading muscle degenerative disease afflicting the elderly, is unknown, although the histopathological features are remarkably similar to those observed in Alzheimer's disease. One leading hypothesis is that the buildup of amyloid-beta (Abeta) peptide within selective skeletal muscle fibers contributes to the degenerative phenotype. Abeta is a small peptide derived via endoproteolysis of the amyloid precursor protein (APP). To determine the pathogenic effect of augmenting Abeta42 levels in skeletal muscle, we used a genetic approach to replace the endogenous wild-type presenilin-1 (PS1) allele with the PS1(M146V) allele in MCK-APP mice. Although APP transgene expression was unaltered, Abeta levels, particularly Abeta42, were elevated in skeletal muscle of the double transgenic (MCK-APP/PS1) mice compared to the parental MCK-APP line. Elevated phospho-tau accumulation was found in the MCK-APP/PS1 mice, and the greater activation of GSK-3beta and cdk5 were observed. Other IBM-like pathological features, such as inclusion bodies and inflammatory infiltrates, were more severe and prominent in the MCK-APP/PS1 mice. Motor coordination and balance were more adversely affected and manifested at an earlier age in the MCK-APP/PS1 mice. The data presented here provide experimental evidence that Abeta42 plays a proximal and critical role in the muscle degenerative process.

1 Bookmark
 · 
56 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuronal loss as a consequence of brain injury, stroke and neurodegenerative disorders causes functional impairments ranging from cognitive impairments to physical disabilities. Extensive rehabilitation and train-ing may lead to neuroprotection and promote functional recovery, although little is known about the molecu-lar and cellular mechanisms driving this event. To investigate the underlying mechanisms and levels of func-tional recovery elicited by repeated physical training or environmental enrichment, we generated an induc-ible mouse model of selective CA1 hippocampal neuronal loss. Following the CA1 neuronal injury, mice underwent one of the above mentioned conditions for 3 months. Exposure to either of these stimuli promoted functional cognitive recovery, which was associated with increased neurogenesis in the subgranular zone of dentate gyrus and enhanced synaptogenesis in the CA1 subfield. Notably, a significant correlation was found between the functional recovery and increased synaptogenesis among survived CA1 neurons. Collectively, these results support the utilization of cognitive and physical stimulation as approaches to promote recovery after neuronal loss and demonstrate the potential of this novel mouse model for the development of therapeu-tic strategies for various neurological disorders associated with focal neuronal loss.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Sporadic inclusion body myositis (sIBM) is the most frequently acquired myopathy in patients over 50 years of age. It is imperative that neurologists and rheumatologists recognize this disorder which may, through clinical and pathological similarities, mimic other myopathies, especially polymyositis. Whereas polymyositis responds to immunosuppressant drug therapy, sIBM responds poorly, if at all. Controversy reigns as to whether sIBM is primarily an inflammatory or a degenerative myopathy, the distinction being vitally important in terms of directing research for effective specific therapies. We review here the pros and the cons for the respective hypotheses. A possible scenario, which our experience leads us to favour, is that sIBM may start with inflammation within muscle. The rush of leukocytes attracted by chemokines and cytokines may induce fibre injury and HLA-I overexpression. If the protein degradation systems are overloaded (possibly due to genetic predisposition, particular HLA-I subtypes or ageing), amyloid and other protein deposits may appear within muscle fibres, reinforcing the myopathic process in a vicious circle.
    Acta Neuropathologica 01/2015; DOI:10.1007/s00401-015-1384-5 · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sporadic inclusion-body myositis (sIBM) presents in average at the sixth decade of life and affects three men for one woman. It is a non-lethal, slowly progressive but disabling disease. Except the striated muscles, no other organs (such as the interstitial lung) are involved. The phenotype of this myopathy is particular since it involves the axial muscles (camptocormia, swallowing dysfunction) and limb girdle (notably the quadriceps) but also the distal muscles (in particular the fingers’ and wrists’ flexors) in a bilateral but non-symmetrical manner. The clinical presentation is then very suggestive of the diagnosis, which remains to be proven by a muscle biopsy. Histological features defining the diagnosis associate endomysial inflammatory infiltrates with frequent invaded fibres (the myositis) and amyloid deposits generally accompanying rimmed vacuoles (the inclusions). There is still today a debate to know if this disease is at its beginning a degenerative or an auto-immune condition. Nonetheless, usual immunosuppressive drugs (corticosteroids, azathioprine, methotrexate) or polyvalent immunoglobulines remain ineffective and even may worsen the handicap. Some controlled randomized trials will soon be launched for this condition, but for now, the best therapeutic approach to slow down the rapidity of progression of the disease is to maintain muscle exercise with the help of the physiotherapists.
    La Revue de Médecine Interne 07/2014; 35(7):472–479. DOI:10.1016/j.revmed.2013.09.001 · 1.32 Impact Factor

Full-text (2 Sources)

Download
8 Downloads
Available from
Dec 1, 2014