Mitochondrial perturbation drives tau oligomers pathology in Alzheimer’s disease

Abstract Tau oligomers, prior to neurofibrillary tangle formation, are toxic species responsible for tau pathology, mitochondrial and synaptic damage, and memory impairment. The underlying mechanisms of abnormal tau accumulation and strategies to eliminate them remain largely unknown. The present study addresses whether mitochondrial reactive oxygen species (ROS) are major contributing factors for tau oligomer formation and, if so, whether eliminating mitochondrial ROS reduces accumulation of tau oligomers and improves mitochondrial and cognitive function in Alzheimer’s disease (AD). First, we determined whether increased oxidative stress correlates with aggregation of tau oligomers in human AD-affected brains, Aβ/tau overexpressed mouse models, human trans-mitochondrial “cybrid” (cytoplasmic hybrid) neuronal cells containing mild cognitive impairment (MCI) and AD-derived mitochondria, and Aβ/tau expressing neuronal cells. In P301S tau and AD mice, upregulation of tau oligomers correlates with ROS accumulation. Elevated tau oligomer levels are also correlated with elevated ROS levels in the AD patient hippocampus. Importantly, human cybrid cells, whose mitochondria are derived from platelets of patients with sporadic AD or MCI, displayed aggregated tau oligomers, which also correlated with upregulated ROS levels. Application of mito-Tempo, a mitochondria-targeted antioxidant, to inhibit the generation of mitochondrial and intracellular ROS in tau and AD neurons, as well as in MCI and AD cybrids ex vivo, leads to a striking decrease in tau oligomers. Finally, in AD mice, mito-Tempo inhibited tau oligomer accumulation and improved behavioral deficiency. Our work adds to the growing body of evidence that oxidative stress contributes to tau oligomer formation and that inhibition of oxidative stress ameliorates tauopathy in AD.