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Updated: Dec 11, 2025
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Mitochondrial DNA Manipulations Affect Tau Oligomerization
Ian W Weidling1,2,3, Heather M Wilkins1,2, Scott J Koppel1,2,3
1University of Kansas Alzheimer's Disease Center; the University of Kansas Medical Center, Kansas City, KS, USA.
Background:
Mitochondrial dysfunction and tau aggregation occur in Alzheimer's disease (AD), and exposing cells or rodents to mitochondrial toxins alters their tau.
Objective:
To further explore how mitochondria influence tau, we measured tau oligomer levels in human neuronal SH-SY5Y cells with different mitochondrial DNA (mtDNA) manipulations.
Methods:
Specifically, we analyzed cells undergoing ethidium bromide-induced acute mtDNA depletion, ρ0 cells with chronic mtDNA depletion, and cytoplasmic hybrid (cybrid) cell lines containing mtDNA from AD subjects.
Results:
We found cytochrome oxidase activity was particularly sensitive to acute mtDNA depletion, evidence of metabolic re-programming in the ρ0 cells, and a relatively reduced mtDNA content in cybrids generated through AD subject mitochondrial transfer. In each case tau oligomer levels increased, and acutely depleted and AD cybrid cells also showed a monomer to oligomer shift.
Conclusion:
We conclude a cell's mtDNA affects tau oligomerization. Overlapping tau changes across three mtDNA-manipulated models establishes the reproducibility of the phenomenon, and its presence in AD cybrids supports its AD-relevance.
Insights
Mitochondrial DNA (mtDNA) levels influence tau aggregation in brain cells. Reduced mtDNA and dysfunction increase tau oligomerization, suggesting a link to Alzheimer's disease pathogenesis.
Area of Science:
- Neuroscience
- Cell Biology
- Mitochondrial Biology
Background:
- Mitochondrial dysfunction and tau aggregation are hallmarks of Alzheimer's disease (AD).
- Mitochondrial toxins alter tau pathology in cellular and rodent models.
Purpose of the Study:
- To investigate the direct impact of mitochondrial DNA (mtDNA) on tau oligomerization.
- To determine if mtDNA alterations influence tau pathology in human neuronal cells relevant to AD.
Main Methods:
- Human neuronal SH-SY5Y cells were subjected to acute and chronic mtDNA depletion.
- Cell lines with chronic mtDNA depletion (ρ0 cells) were generated.
- Cytoplasmic hybrid (cybrid) cell lines were created using mtDNA from AD subjects.
Main Results:
- Acute mtDNA depletion impaired cytochrome oxidase activity.
- Metabolic reprogramming was observed in ρ0 cells.
- Reduced mtDNA content in AD cybrids correlated with increased tau oligomer levels and a monomer-to-oligomer shift.
Conclusions:
- Cellular mtDNA content directly affects tau oligomerization.
- Consistent tau changes across models confirm reproducibility.
- Findings in AD cybrids support the relevance of mtDNA to AD pathology.
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