Affiliations: [a]
University of Kansas Alzheimer’s Disease Center; the University of Kansas Medical Center, Kansas City, KS, USA
| [b] Departments of Neurology, University of Kansas Medical Center, Kansas City, KS, USA
| [c] Molecular and Integrative Physiology, and University of Kansas Medical Center, Kansas City, KS, USA
| [d] Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA
| [e] Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA
Correspondence:
[*]
Correspondence to: Russell H. Swerdlow, University of Kansas Alzheimer’s Disease Center, 4350 Shawnee Mission Parkway, Fairway, KS 66205, USA. Tel.: +1 913 588 0555; Fax: +1 913 588 0681; E-mail: rswerdlow@kumc.edu.
Abstract: 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.
Keywords: Alzheimer’s disease, mitochondria, mitochondrial DNA, oligomers, tau
