TRANSFER OF BETA-AMYLOID PRECURSOR PROTEIN GENE USING ADENOVIRUS VECTOR CAUSES MITOCHONDRIAL ABNORMALITIES IN CULTURED NORMAL HUMAN MUSCLE

As in Alzheimer-disease (AD) brain, vacuolated muscle fibers of inclus ion-body myositis (IBIM) contain abnormally accumulated beta-amyloid p recursor protein (beta APP), including its beta-amyloid protein epitop e, and increased beta APP-751 mRNA, Other similarities between IBM mus cle and AD brain phenotypes include paired helical filaments, hyperpho sphorylated tau protein, apolipoprotein E, and mitochondrial abnormali ties, including decreased cytochrome-c oxidase (COX) activity, The pat hogenesis of these abnormalities in IBIM muscle and AD brain is not kn own, We now report that direct transfer of the beta APP gene, using ad enovirus vector, into cultured normal human muscle fibers causes struc tural abnormalities of mitochondria and decreased COX activity, In thi s adenovirus-mediated beta APP gene transfer, we demonstrated that bet a APP overproduction can induce mitochondrial abnormalities, The data suggest that excessive beta APP may be responsible for mitochondrial a nd COX abnormalities in IBM muscle and perhaps AD brain.