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Mitochondrial genomic contribution to mitochondrial dysfunction in Alzheimer's disease
Isaac Onyango1, Shaharyar Khan, Bradley Miller
1Center for the Study of Neurodegenerative Diseases, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Journal of Alzheimer'S Disease : JAD
|July 29, 2006
Summary
Mitochondrial DNA (mtDNA) from Alzheimer's disease (AD) patients may contribute to disease pathology. Cybrid models show that AD patient mtDNA can cause mitochondrial dysfunction and increased oxidative stress in neural cells, suggesting a potential role in AD progression.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Genetics
Background:
- Alzheimer's disease (AD) is characterized by mitochondrial dysfunction and oxidative stress, but the origins and causal links remain unclear.
- Previous studies have largely failed to identify consistent mitochondrial DNA (mtDNA) mutations in AD brains, beyond age-related changes.
- Oxidative damage to mtDNA in AD brains is elevated, suggesting potential for mutations and transcriptional issues.
Purpose of the Study:
- To investigate the role of mitochondrial DNA (mtDNA) in Alzheimer's disease (AD) pathogenesis.
- To determine if mtDNA from AD patients can transmit disease-related cellular dysfunction.
- To explore novel methods for examining mtDNA's contribution to AD in brain cells.
Main Methods:
- Utilized cybrid (cytoplasmic hybrid) models, transferring mtDNA from AD patients' platelets into mtDNA-depleted human neural cells (rho(0) cells).
- Examined cellular consequences including cytochrome oxidase activity, oxidative stress levels, beta-amyloid production, and intracellular signaling pathways.
- Proposed novel protein transfection technology ('protofection') for direct mtDNA transfer into neuronal mitochondria.
Main Results:
- Expression of AD patient mtDNA in cybrid cells resulted in decreased cytochrome oxidase activity and increased oxidative stress.
- AD patient mtDNA also led to increased beta-amyloid production, activation of caspases, and accelerated mtDNA proliferation.
- Abnormal mitochondrial morphology and transport were observed in cybrid cells carrying AD patient mtDNA.
Conclusions:
- Mitochondrial DNA (mtDNA) from living AD patients can transmit cellular dysfunction, including mitochondrial impairment and oxidative stress, to neural cells.
- These findings suggest a potential causal role for altered mtDNA in Alzheimer's disease pathogenesis.
- Further investigation using advanced techniques like protofection is needed to confirm mtDNA's contribution in the AD brain, acknowledging likely heterogeneity.
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