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 inclusion-body myositis (IBM) contain abnormally accumulated beta-amyloid precursor protein (beta APP), including its beta-amyloid protein epitope, and increased beta APP-751 mRNA. Other similarities between IBM muscle and AD brain phenotypes include paired helical filaments, hyperphosphorylated tau protein, apolipoprotein E, and mitochondrial abnormalities, including decreased cytochrome-c oxidase (COX) activity. The pathogenesis of these abnormalities in IBM muscle and AD brain is not known. We now report that direct transfer of the beta APP gene, using adenovirus vector, into cultured normal human muscle fibers causes structural abnormalities of mitochondria and decreased COX activity. In this adenovirus-mediated beta APP gene transfer, we demonstrated that beta APP overproduction can induce mitochondrial abnormalities. The data suggest that excessive beta APP may be responsible for mitochondrial and COX abnormalities in IBM muscle and perhaps AD brain.
Askanas
V
V
Department of Neurology, University of Southern California School of Medicine, Good Samaritan Hospital, Los Angeles 90017, USA.
McFerrin
J
J
Baqué
S
S
Alvarez
R B
RB
Sarkozi
E
E
Engel
W K
WK
D000256:Adenoviridae; D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D001706:Biopsy; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D003576:Electron Transport Complex IV / Q000032:analysis; D000939:Epitopes / Q000032:analysis; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors; D006801:Humans; D017403:In Situ Hybridization; D008854:Microscopy, Electron; D008931:Mitochondria, Muscle / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure*; D018485:Muscle Fibers, Skeletal / Q000502:physiology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D000939:Epitopes; D012333:RNA, Messenger; D011994:Recombinant Proteins; D003576:Electron Transport Complex IV