Genetically Augmenting A ␤ 42 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: 4.59). 07/2006; 168(6):1986-97. DOI: 10.2353/ajpath.2006.051232
Source: PubMed


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.

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Available from: Kim N Green, Dec 01, 2014
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    • "Biopsy analysis of the diseased tissue shows vacuolated muscle fibers containing deposits of ubiquitin-positive aggregates of misfolded proteins, including Aβ and phosphorylated tau, which display amyloid signatures, together with remarkable inflammation, similar to AD and other neurodegenerative pathologies [13], [14]. The importance of Aβ levels for disease development and progression of muscle degeneration was also supported by a study on transgenic mice engineered so as to produce increased amounts of Aβ42 in the muscle tissue [15]. "
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    ABSTRACT: The presence of amyloid aggregates of the 42 amino acid peptide of amyloid beta (Aβ42) in the brain is the characteristic feature of Alzheimer's disease (AD). Amyloid beta (Aβ deposition is also found in muscle fibers of individuals affected by inclusion body myositis (sIBM), a rare muscular degenerative disease affecting people over 50. Both conditions are presently lacking an effective therapeutic treatment. There is increasing evidence to suggest that natural polyphenols may prevent the formation of toxic amyloid aggregates; this applies also to oleuropein aglycone (OLE), the most abundant polyphenol in extra virgin olive oil, previously shown to hinder amylin and Aβ aggregation. Here we evaluated the ability of OLE to interfere with Aβ proteotoxicity in vivo by using the transgenic CL2006 and CL4176 strains of Caenorhabditis elegans, simplified models of AD and of sIBM, which express human Aβ in the cytoplasm of body wall muscle cells. OLE-fed CL2006 worms displayed reduced Aβ plaque deposition, less abundant toxic Aβ oligomers, remarkably decreased paralysis and increased lifespan with respect to untreated animals. A protective effect was also observed in CL4176 worms but only when OLE was administered before the induction of the Aβ transgene expression. These effects were specific, dose-related, and not mediated by the known polyphenolic anti-oxidant activity, suggesting that, in this model organism, OLE interferes with the Aβ aggregation skipping the appearance of toxic species, as already shown in vitro for Aβ42.
    PLoS ONE 03/2013; 8(3):e58893. DOI:10.1371/journal.pone.0058893 · 3.23 Impact Factor
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    • "Not reported Not reported ↓ Sugarman et al., 2002; Kitazawa et al., 2006 "
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    ABSTRACT: The discovery of gene mutations underlying autosomal dominant Alzheimer's disease has enabled researchers to reproduce several hallmarks of this disorder in transgenic mice, notably the formation of Aβ plaques in brain and cognitive deficits. APP transgenic mutants have also been investigated with respect to survival rates, neurologic functions, and motor coordination, which are all susceptible to alteration in Alzheimer dementia. Several transgenic lines expressing human mutated or wild-type APP had higher mortality rates than non-transgenic controls with or without the presence of Aβ plaques. Mortality rates were also elevated in APP transgenic mice with vascular amyloid accumulation, thereby implicating cerebrovascular factors in the precocious death observed in all APP transgenic models. In addition, myoclonic jumping has been described in APP mutants, together with seizure activity, abnormal limb-flexion and paw-clasping reflexes, and motor coordination deficits. The neurologic signs resemble the myoclonic movements, epileptic seizures, pathological reflexes, and gait problems observed in late-stage Alzheimer's disease.
    Reviews in the neurosciences 08/2012; 23(4):363-79. DOI:10.1515/revneuro-2012-0041 · 3.33 Impact Factor
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    • "As mentioned in section 2.2.1, one model with the APP Swedish mutation express APP in skeletal muscle (Sugarman et al., 2002). These mice were crossed with homozygous PS1/ M146V knock-in mice, forming a bigenic APP/SWE/Ckm model (Sugarman et al., 2002; Guo et al. 1999; Kitazawa et al. 2006), with higher than normal Aβ42 levels and phosphorylated tau in skeletal muscle with infiltrates of CD8-immunoreactive T cells (Kitazawa et al. 2006). "
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    ABSTRACT: The discovery of gene mutations responsible for autosomal dominant Alzheimer's disease has enabled researchers to reproduce in transgenic mice several hallmarks of this disorder, notably Aβ accumulation, though in most cases without neurofibrillary tangles. Mice expressing mutated and wild-type APP as well as C-terminal fragments of APP exhibit variations in exploratory activity reminiscent of behavioural and psychological symptoms of Alzheimer dementia (BPSD). In particular, open-field, spontaneous alternation, and elevated plus-maze tasks as well as aggression are modified in several APP transgenic mice relative to non-transgenic controls. However, depending on the precise murine models, changes in open-field and elevated plus-maze exploration occur in either direction, either increased or decreased relative to controls. It remains to be determined which neurotransmitter changes are responsible for this variability, in particular with respect to GABA, 5HT, and dopamine.
    Neuroscience & Biobehavioral Reviews 02/2012; 36(5):1357-75. DOI:10.1016/j.neubiorev.2012.02.011 · 8.80 Impact Factor
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