Introduction: Tau-mediated toxicity in Alzheimer's disease is thought to operate through low-n oligomers, rather than filamentous aggregates. However, the nature of oligomers and pathways of toxicity are poorly understood. Therefore, we investigated structural and functional aspects of highly purified oligomers of a pro-aggregant tau species.
Methods: Purified oligomers of the tau repeat domain were characterized by biophysical and structural methods. Functional aspects were investigated by cellular assays ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of cell viability, lactate dehydrogenase release assay [for cell toxicity], reactive oxygen species production, and calcium assay), combined with analysis of neuronal dendritic spines exposed to oligomers.
Results: Purified low-n oligomers are roughly globular, with sizes around 1.6 to 5.4 nm, exhibit an altered conformation, but do not have substantial β-structure. Treatment of primary neurons with oligomers impairs spine morphology and density, accompanied by increased reactive oxygen species and intracellular calcium, but without affecting cell viability (by (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of cell viability and lactate dehydrogenase release assay [for cell toxicity]).
Discussion: Tau oligomers are toxic to synapses but not lethal to cells.
Keywords: Calcium elevation; Neurons; Oligomers; ROS production; Structure; Synapses; Tau; Toxicity; Transgenic mouse brain-derived oligomers.
Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.