Does Overexpression of βAPP in Aging Muscle Have a Pathogenic Role and a Relevance to Alzheimer’s Disease? : Clues from Inclusion Body Myositis, Cultured Human Muscle, and Transgenic Mice

In Alzheimer’s disease (AD) pathogenesis, an underlying βAPP/Aβ dysmetabolism leading to neuronal toxicity is considered the essential abnormality by most investigators. 1-4 Hyperphosphorylation and filamentogenesis of tau into paired helical filaments (PHFs) is also thought to be important 5,6 and apolipoprotein E4 genotype is considered an aggravating factor. 7 The various hypotheses for sporadic AD (s-AD) acknowledge the milieu of aging brain cells but usually omit consideration of an initial sparking event. For several years it was presumed that βAPP/Aβ and tau abnormalities occur only in the brain (and its blood vessels in regard to βAPP/Aβ), until βAPP, Aβ, and PHFs containing hyperphosphorylated tau were shown to accumulate pathologically within abnormal muscle fibers of two closely related, progressively disabling muscle diseases, sporadic inclusion-body myositis (s-IBM) and hereditary inclusion-body myopathy (h-IBM). 8-10 s-IBM is a disease of aging muscle with clinical onset nearly always at age 50 or older; h-IBM begins clinically at ages 15–30 in young adult muscle. 11 The autosomal-recessive form of h-IBM is caused by a yet-undetermined gene on chromosome 9 p1-q1, 12,13 not a defect of the βAPP gene on chromosome 21; in two families with the autosomal-dominant form of h-IBM, no defect of the βAPP-gene was demonstrable. 14 s-IBM is the most common muscle disease in older patients. h-IBM is rather rare, but probably more common than hereditary AD (h-AD). In s-IBM and h-IBM it was shown that βAPP-mRNA was overexpressed in muscle fibers 15 (but not exclusively; cellular prion protein and its mRNA were also overexpressed). 16 Several other “Alzheimer characteristic” proteins, including presenilin-1 and proteins related to oxidative stress, also accumulated within abnormal muscle fibers of s-IBM and h-IBM. 11,17,18 Intracellular congophilic amyloid deposits are another characteristic and consistent feature of s-IBM muscle fibers. 8,19 In h-IBM they are very rare in younger patients, but their occurrence, especially in autosomal-dominant forms, increases in older patients. 11 The intracellular amyloid of the IBMs is of two structural-chemical types: collections of 15- to 21-nm PHFs containing immunoreactive tau (and other components, but not Aβ), and collections (“microplaquettes”) containing 6- to 10-nm filaments immunoreactive for Aβ. 11 Because the same proteins accumulate within s- and h-IBM muscle fibers as accumulate in the brains of patients with sporadic and hereditary forms of AD, the muscle and brain diseases might share certain pathogenic steps and knowledge of one disease might help elucidate the other. Cellular aging and evidence of oxidative stress are associated with the IBMs and the ADs. The IBMs and the ADs are both multifactorial and polygenetic. The respective cascades of events leading to the specific form of AD-like IBM muscle fiber degeneration and the similar specific features in AD brain are not understood. Within both the IBM and the AD categories, the pathological phenotypes of sporadic and hereditary forms are very similar, despite the different direct causes being mainly nongenetic versus mainly genetic. Therefore, in each disease category it has been proposed, by our group for the IBMs 20,21 and by others for the ADs, 22,23 that different etiologies including different genetic defects in the hereditary forms lead to the same upstream step, which then promotes the final common downstream pathogenic cascade of events resulting in the specific cellular deterioration. Moreover, the intracellular pathogenic cascades of the IBMs and the ADs might have strong similarities following determination by yet-unknown factors of the initial tissue selectivity in each category, muscle versus brain. In both s-IBM and h-IBM, it is of particular interest that individual muscle fibers accumulate N- and C-terminal βAPP and Aβ, and βAPP-mRNA, before other abnormalities are evident. 8-11 We hypothesized that overexpression of βAPP might be upstream to other cellular abnormalities, including oxidative stress and mitochondrial abnormalities (Figure 1) ▶ . 21 To test this hypothesis, wild-type full-length 751 βAPP was overexpressed long-term in cultured normal human muscle. It produced within muscle fibers several aspects of the IBM cellular phenotype, including vacuolization, congophilic amyloid inclusions (as microplaquettes) in a small percentage of muscle fibers, cytoplasmic 6- to 10-nm amyloid-like filaments, nuclear PHFs, mitochondrial cytochrome oxidase deficiency, and mitochondrial morphological abnormalities. 24,25 Figure 1. Genetic defects in h-IBM and various factors (including a putative virus) in s-IBM lead to presently unknown mechanisms [“?” box in diagram]. These up-regulate βAPP transcription, resulting in βAPP overexpression. ...