Title
Extracellular low-n oligomers of tau cause selective synaptotoxicity without affecting cell viability
Author
Senthilvelrajan Kaniyappan, Ram Reddy Chandupatla, Eva-Maria Mandelkow, Eckhard Mandelkow
Year
2017
Journal
Alzheimer's & Dementia
Abstract
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. 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. 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]). Tau oligomers are toxic to synapses but not lethal to cells.
Instrument
J-810
Keywords
Circular dichroism, Secondary structure, Aggregation, Biochemistry