Mitochondrial oxidative stress contributes to the pathological aggregation and accumulation of tau oligomers in Alzheimer's disease. Issue 15 (15th February 2022)

• Record Type: Journal Article
• Authors: Du, Fang; Yu, Qing; Kanaan, Nicholas M; Yan, Shirley ShiDu
• Is Part Of: Human molecular genetics. Volume 31:Issue 15(2022)
• Page Start: 2498
• Page End: 2507
• Publication Date: 2022-02-15
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddab363
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: Tau oligomers (oTau) are thought to precede neurofibrillary tangle formation and likely represent one of the toxic species in disease. This study addresses whether mitochondrial reactive oxygen species (ROS) contribute to tau oligomer accumulation. First, we determined whether elevated oxidative stress correlates with aggregation of tau oligomers in the brain and platelets of human Alzheimer's disease (AD) patient, tauopathy mice, primary cortical neurons from tau mice and human trans-mitochondrial 'cybrid' (cytoplasmic hybrid) neuronal cells, whose mitochondria are derived from platelets of patients with sporadic AD- or mild cognitive impairment (MCI)-derived mitochondria. Increased formation of tau oligomers correlates with elevated ROS levels in the hippocampi of AD patients and tauopathy mice, AD- and MCI-derived mitochondria and AD and MCI cybrid cells. Furthermore, scavenging ROS by application of mito-TEMPO/2-(2, 2, 6, 6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride, a mitochondria-targeted antioxidant, not only inhibits the generation of mitochondrial ROS and rescues mitochondrial respiratory function but also robustly suppresses tau oligomer accumulation in MCI and AD cybrids as well as cortical neurons from tau mice. These studies provide substantial evidence that mitochondria-mediated oxidative stress contributes to tau oligomer formation and accumulation.