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Transfer of beta-amyloid precursor protein gene using adenovirus vector causes mitochondrial abnormalities in
V Askanas1, J McFerrin, S Baqué
1Department of Neurology, University of Southern California School of Medicine, Good Samaritan Hospital, Los Angeles 90017, USA.
Abstract:
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.
Insights
Beta-amyloid precursor protein (beta APP) overproduction in muscle fibers causes mitochondrial dysfunction, mimicking inclusion-body myositis (IBM) and Alzheimer
Area of Science:
- Neurodegenerative Diseases
- Muscle Biology
- Molecular Genetics
Background:
- Inclusion-body myositis (IBM) muscle fibers share phenotypes with Alzheimer's disease (AD) brain, including beta-amyloid precursor protein (beta APP) accumulation.
- Both conditions exhibit mitochondrial abnormalities, such as decreased cytochrome-c oxidase (COX) activity, but the underlying cause is unknown.
Purpose of the Study:
- To investigate if beta APP overproduction can directly induce mitochondrial abnormalities.
- To explore the role of beta APP in the pathogenesis of IBM muscle and potentially AD brain.
Main Methods:
- Adenovirus vector-mediated gene transfer of beta APP into cultured normal human muscle fibers.
- Analysis of structural mitochondrial abnormalities and COX activity following beta APP gene delivery.
Main Results:
- Direct gene transfer of beta APP into human muscle fibers induced structural mitochondrial abnormalities.
- Beta APP overproduction led to decreased COX activity in cultured muscle fibers.
- These findings demonstrate a causal link between beta APP and mitochondrial dysfunction.
Conclusions:
- Excessive beta APP can directly cause mitochondrial abnormalities and decreased COX activity in muscle.
- The data suggest that beta APP overproduction may be a key factor in the mitochondrial pathology observed in IBM muscle.
- This mechanism might also contribute to mitochondrial dysfunction in Alzheimer's disease brain.