Ian W Weidling1,2,3, Heather M Wilkins1,2, Scott J Koppel1,2,3, Lewis Hutfles1, Xiaowan Wang1,2, Anuradha Kalani1,2, Blaise W Menta1,2,4, Benjamin Ryan1,4, Judit Perez-Ortiz1,2, T Chris Gamblin5, Russell H Swerdlow1,2,3,4. 1. University of Kansas Alzheimer's Disease Center; the University of Kansas Medical Center, Kansas City, KS, USA. 2. Departments of Neurology, University of Kansas Medical Center, Kansas City, KS, USA. 3. Molecular and Integrative Physiology, and University of Kansas Medical Center, Kansas City, KS, USA. 4. Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA. 5. Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA.
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.
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.
Entities:
Keywords:
Alzheimer’s disease; mitochondria; mitochondrial DNA; oligomers; tau
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