Inclusion body myositis-like phenotype induced by transgenic overexpression of βAPP in skeletal muscle

Abstract

Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, although affected muscle fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease. Accumulation of the amyloid-␤ peptide, which is derived from proteolysis of the larger amyloid-␤ precursor protein (␤APP), seems to be an early pathological event in Alzheimer's disease and also in IBM, where in the latter, it predominantly occurs intracellularly within affected myofibers. To elucidate the possible role of ␤APP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which we selectively targeted ␤APP overexpression to skeletal muscle by using the muscle creatine kinase promoter. Here we report that older (>10 months) transgenic mice exhibit intracellular immunoreactivity to ␤APP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of ␤APP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results are consistent with a pathogenic role for ␤APP mismetabolism in human IBM.

AβPP-overexpression and proteasome inhibition increase αB-crystallin in cultured human muscle: Relevance to inclusion-body myositis

“…Abnormal increase of AβPP/Aβ appears to be an early upstream step in the IBM pathogenesis because a) AβPP/Aβ accumulation appears to precede other detected abnormalities ins-IBM muscle fibers [2], and b) several aspects of the IBM phenotype were produced in cultured normal human muscle fibers (CHMFs) after experimental long-term overexpression of AβPP [5][6][7]. Long overexpression of AβPP in muscle of transgenic mice also induced some aspects of the IBM phenotype [8][9][10]. Moreover, increased oligomerization of Aβ was associated with increased degeneration of CHMFs [11].…”

Genetically Augmenting Aβ42 Levels in Skeletal Muscle Exacerbates Inclusion Body Myositis-Like Pathology and Motor Deficits in Transgenic Mice

“…14,21,27 MaxiSorp immunoplates (Nalge Nunc, Rochester, NY) were coated with antibody against A␤1-17 (gift from Dr. William Van Nostrand) at a concentration of 25 g/l, and A␤40 and A␤42 were detected by specific horseradish peroxidase-conjugated antibody against A␤35-40 (MM32-13.1.1) or A␤35-42 (MM40-21.3.4), respectively.…”

Estrogen and Androgen Protection of Human Neurons against Intracellular Amyloid 1-42 Toxicity through Heat Shock Protein 70

“…Intracellular amyloid ␤ 1-42 (iA␤ ) accumulates in the hippocampus and the entorhinal cortex neurons of mildly cognitively impaired and Alzheimer's disease (AD) individuals (Gouras et al, 2000;D'Andrea et al, 2001D'Andrea et al, , 2002Takahashi et al, 2002), in Down's syndrome brain neurons (Gyure et al, 2001;Busciglio et al, 2002), and in inclusion body myositis muscle cells (Querfurth et al, 2001;Sugarman et al, 2002). In AD, the accumulation of iA␤ 1-42 precedes amyloid plaque formation (Gouras et al, 2000;D'Andrea et al, 2001).…”